Substituted gamma lactams as therapeutic agents

ABSTRACT

A compound comprising 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, prodrug, or a metabolite thereof is disclosed herein. Y, A, and B are as described herein. 
     Methods, compositions, and medicaments related to these compounds are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.12/323,077, filed Nov. 25, 2008, which is a Continuation of U.S. patentapplication Ser. No. 10/599,046, filed Jun. 29, 2007, which is aNational Stage Application under 35 U.S.C. 371 of PCT applicationPCT/US/2006/007797, filed Mar. 6, 2006, which claims the benefit ofProvisional Application No. 60/660,748, filed on Mar. 10, 2005, thecontents of which are incorporated by reference in their entirety.

DESCRIPTION OF RELATED ART

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives are currently commerciallyavailable for use in glaucoma management. Eicosanoids and derivativesinclude numerous biologically important compounds such as prostaglandinsand their derivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by a or [e.g. prostaglandin F_(2α)(PGF_(2β)]).

Prostaglandin EP₂ selective agonists are believed to have severalmedical uses. For example, U.S. Pat. No. 6,437,146 teaches the use ofprostaglandin EP₂ selective agonists “for treating or preventinginflammation and pain in joint and muscle (e.g., rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenilearthritis, etc.), inflammatory skin condition (e.g., sunburn, burns,eczema, dermatitis, etc.), inflammatory eye condition (e.g.,conjunctivitis, etc.), lung disorder in which inflammation is involved(e.g., asthma, bronchitis, pigeon fancier's disease, farmer's lung,etc.), condition of the gastrointestinal tract associated withinflammation (e.g., aphthous ulcer, Chrohn's disease, atrophicgastritis, gastritis varialoforme, ulcerative colitis, coeliac disease,regional ileitis, irritable bowel syndrome, etc.), gingivitis,inflammation, pain and tumescence after operation or injury, pyrexia,pain and other conditions associated with inflammation, allergicdisease, systemic lupus crythematosus, scleroderma, polymyositis,tendinitis, bursitis, periarteritis nodose, rheumatic fever, Sjgren'ssyndrome, Behcet disease, thyroiditis, type I diabetes, diabeticcomplication (diabetic microangiopathy, diabetic retinopathy, diabeticneohropathy, etc.), nephrotic syndrome, aplastic anemia, myastheniagravis, uveitis contact dermatitis, psoriasis, Kawasaki disease,sarcoidosis, Hodgkin's disease, Alzheimers disease, kidney dysfunction(nephritis, nephritic syndrome, etc.), liver dysfunction (hepatitis,cirrhosis, etc.), gastrointestinal dysfunction (diarrhea, inflammatorybowel disease, etc.) shock, bone disease characterized by abnormal bonemetabolism such as osteoporosis (especially, postmenopausalosteoporosis), hypercalcemia, hyperparathyroidism, Paget's bonediseases, osteolysis, hypercalcemia of malignancy with or without bonemetastases, rheumatoid arthritis, periodonritis, osteoarthritis,ostealgia, osteopenia, cancer cachexia, calculosis, lithiasis(especially, urolithiasis), solid carcinoma, mesangial proliferativeglomerulonephritis, edema (e.g. cardiac edema, cerebral edema, etc.),hypertension such as malignant hypertension or the like, premenstrualtension, urinary calculus, oliguria such as the one caused by acute orchronic failure, hyperphosphaturia, or the like.”

U.S. Pat. No 6,710,072 teaches the use of EP2 agonists for the treatmentor prevention of “osteoporosis, constipation, renal disorders, sexualdysfunction, baldness, diabetes, cancer and in disorder of immuneregulation . . . various pathophysiological diseases including acutemyocardial infarction, vascular thrombosis, hypertension, pulmonaryhypertension, ischemic heart disease, congestive heart failure, andangina pectoris.”

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIGS. 1-16 show examples of methods that can be used to prepare thecompounds disclosed herein.

DESCRIPTION OF THE INVENTION

A compound is disclosed herein comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein Y is an organic acid functional group, or an amide or ester    thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or    an ether thereof comprising up to 12 carbon atoms; or Y is a    tetrazolyl functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is aryl or heteroaryl.

Y is an organic acid functional group, or an amide or ester thereofcomprising up to 12 carbon atoms; or Y is hydroxymethyl or an etherthereof comprising up to 12 carbon atoms; or Y is a tetrazolylfunctional group.

An organic acid functional group is an acidic functional group on anorganic molecule. While not intending to be limiting, organic acidfunctional groups may comprise an oxide of carbon, sulfur, orphosphorous. Thus, while not intending to limit the scope of theinvention in any way, in certain compounds Y is a carboxylic acid,sulfonic acid, or phosphonic acid functional group, i.e. one of thestructures shown below.

Salts of any of these acids of any pharmaceutically acceptable form arealso contemplated.

In some embodiments, esters contemplated in the practice of theinvention are C₁ to C₆ esters. In other embodiments, esters contemplatedin the practice of the invention are C₃ esters. In certain embodiments,esters contemplated in the practice of the invention are isopropylesters

Additionally, an amide or ester of one of the organic acids shown abovecomprising up to 12 carbon atoms is also contemplated. In an ester, ahydrocarbyl moiety replaces a hydrogen atom of an acid such as in acarboxylic acid ester, e.g. CO₂Me, CO₂Et, etc.

In an amide, an amine group replaces an OH of the acid. Examples ofamides include CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, and CONH(CH₂CH₂OH)where R² is independently H, C₁-C₆ alkyl, phenyl, or biphenyl. Moietiessuch as CONHSO₂R² are also amides of the carboxylic acid notwithstandingthe fact that they may also be considered to be amides of the sulfonicacid R²—SO₃H.

While not intending to limit the scope of the invention in any way, Ymay also be hydroxymethyl or an ether thereof comprising up to 12 carbonatoms. Thus, compounds having a structure shown below are possible.

Additionally, ethers of these compounds are also possible. An ether is afunctional group wherein a hydrogen of an hydroxyl is replaced bycarbon, e.g., Y is CH₂OCH₃, CH₂OCH₂CH₃, etc.

Finally, while not intending to limit the scope of the invention in anyway, Y may be a tetrazolyl functional group, such as compounds having astructure according to the formula below.

An unsubstituted tetrazolyl functional group has two tautomeric forms,which can rapidly interconvert in aqueous or biological media, and arethus equivalent to one another. These tautomers are shown below.

Additionally, if R² is C₁-C₆ alkyl, phenyl, or biphenyl, other isomericforms of the tetrazolyl functional group such as the one shown below arealso possible, unsubstituted and hydrocarbyl substituted tetrazolyl upto C₁₂ are considered to be within the scope of the term “tetrazolyl.”

While not intending to limit the scope of the invention in any way, inone embodiment, Y is selected from the group consisting of CO₂(R²),CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂,CONHSO₂R², SO₂N(R²)₂, SO₂NHR², and tetrazolyl-R²; wherein R² isindependently H, C₁-C₆ alkyl, phenyl, or biphenyl.

In another embodiment Y is not CONH-phenyl or CONH-cyclohexyl.

In relation to the identity of A disclosed in the chemical structurespresented herein, A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with Sor O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is from 1 to 4, and wherein oneCH₂ may be substituted with S or O.

While not intending to be limiting, A may be —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is substituted with S and/or O. For example,while not intending to limit the scope of the invention in any way, Amay be an S substituted moiety such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may be an O substituted moiety such as one of thefollowing or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may have both an O and an S substituted into the chain,such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(o)— whereinAr is interarylene or heterointerarylene, the sum of m and o is from 1to 4, and wherein one CH, may be substituted with S or O. In otherwords, while not intending to limit the scope of the invention in anyway,

-   in one embodiment A comprises from 1 to 4 CH₂ moieties and Ar, e.g.    —CH₂—Ar—, —(CH₂)₂—Ar—, —CH₂—Ar—CH₂—, —CH₂—Ar—(CH₂)₂—,    —(CH₂)₂—Ar—(CH₂)₂—, and the like; or-   A comprises O, from 0 to 3 CH₂ moieties, and Ar, e.g., —O—Ar—,    Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —O—CH₂—Ar—, —O—CH₂—Ar—(CH₂)₂, and the    like; or-   A comprises S, from 0 to 3 CH₂ moieties, and Ar, e.g., —S—Ar—,    Ar—CH₂—S—, —S—Ar—(CH₂)₂—, —S—CH₂—Ar—, —S—CH₂—Ar—(CH₂)₂,    —(CH₂)₂—S—Ar, and the like.

In another embodiment, the sum of m and o is from 2 to 4 wherein one CH₂may be substituted with S or O.

In another embodiment, the sum of m and o is 3 wherein one CH₂ may besubstituted with S or O.

In another embodiment, the sum of m and o is 2 wherein one CH₂ may besubstituted with S or O.

In another embodiment, the sum of m and o is 4 wherein one CH₂ may besubstituted with S or O.

Interarylene or heterointerarylene refers to an aryl ring or ring systemor a heteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene or heterointerarylene may be substituted orunsubstituted. Unsubstituted interarylene or heterointerarylene has nosubstituents other than the two parts of the molecule it connects.Substituted interarylene or heterointerarylene has one or moresubstitutuents in addition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. In another embodiment Ar is interphenylene (Ph). Inanother embodiment A is —(CH₂)₂-Ph-. While not intending to limit scopeof the invention in any way, substituents may have 4 or less heavyatoms, or in other words, non hydrogen atoms. Any number of hydrogenatoms required for a particular substituent will also be included. Thus,the substituent may be

-   hydrocarbyl, i.e. a moiety consisting of only carbon and hydrogen    such as alkyl, having up to 4 carbon atoms, including alkyl up to    C₄, alkenyl, alkynyl, and the like;-   hydrocarbyloxy up to C₃;-   CF₃;-   halo, such as F, Cl, or Br;-   hydroxyl;-   NH₂ and alkylamine functional groups up to C₃;-   other N or S containing substituents;-   and the like.

Substituted interarylene or interheteroarylene may have one or moresubstituents, up to as many as the ring or ring system will bear, andthe substituents may be the same or different. Thus, for example, aninterarylene ring or interheteroarylene ring may be substituted withchloro and methyl; methyl, OH, and F; CN, NO₂, and ethyl; and the likeincluding any conceivable substituent or combination of substituentpossible in light of this disclosure.

In one embodiment A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar isinterphenylene, the sum of m and o is from 1 to 3, and wherein one CH₂may be substituted with S or O.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂—Ar—OCH₂— and Ar is interphenylene. In another embodiment, Ar is 1,3interaryl or interheteroaryl, where Ar attached at the 1 and 3positions, such as when A has the structure shown below.

Other examples of 1,3 interaryl or interheteroaryl are exemplified inthe following examples of A-Y.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with Sor O; or A is —(CH₂)₂-Ph- wherein one CH₂ may be substituted with S orO.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with Sor O; or A is —(CH₂)₂-Ph-.

In another embodiment A is not —(CH₂)₆—.

In other embodiments, A has one of the following structures, where Y isattached to the oxazolyl or thiazolyl ring.

In other embodiments A is one of the structures shown below, where Y isattached to the phenyl or heteroaryl ring.

In another embodiment A is —CH₂OCH₂Ar.

In another embodiment A is —CH₂SCH₂Ar.

In another embodiment A is —(CH₂)₃Ar.

In another embodiment A is —CH₂O(CH₂)₄.

In another embodiment A is —CH₂S(CH₂)₄.

In another embodiment A is, —S(CH₂)₃S(CH₂)₂—.

In another embodiment A is, —(CH₂)₄OCH₂—.

In another embodiment A is, cis —CH₂CH═CH—CH₂OCH₂—.

In another embodiment A is, —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is, —(CH₂)₂S(CH₂)₃—.

In another embodiment A is, —CH₂-Ph-OCH₂—, wherein Ph is interphenylene.

In another embodiment A is, —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene.

In another embodiment A is, —CH₂—O—(CH₂)₄—.

In another embodiment A is, —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is, —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

B is aryl or heteroaryl.

Aryl is an unsubstituted or substituted aromatic ring or ring systemsuch as phenyl, naphthyl, biphenyl, and the like.

Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i.e.a ring carbon is substituted by N, O, or S. While not intending to belimiting, examples of heteroaryl include unsubstituted or substitutedthienyl, pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl,indolyl, and the like.

The substituents of aryl or heteroaryl may have up to 12 non-hydrogenatoms each and as many hydrogen atoms as necessary. Thus, while notintending to limit the scope of the invention in any way, thesubstituents may be:

-   hydrocarbyl, i.e. a moiety consisting of only carbon and hydrogen    such as alkyl, alkenyl, alkynyl, and the like, including linear,    branched or cyclic hydrocarbyl, and combinations thereof;-   hydrocarbyloxy, meaning O-hydrocarbyl such as OCH₃, OCH₂CH₃,    O-cyclohexyl, etc, up to 11 carbon atoms;-   other ether substituents such as CH₂OCH₃, (CH₂)₂OCH(CH₃)₂, and the    like;-   thioether substituents including S-hydrocarbyl and other thioether    substituents; hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as    CH₂OH, C(CH₃)₂OH, etc, up to 11 carbon atoms;-   nitrogen substituents such as NO₂, CN, and the like, including-   amino, such as NH₂, NH(CH₂CH₃OH), NHCH₃, and the like up to 11    carbon atoms;-   carbonyl substituents, such as CO₂H, ester, amide, and the like;-   halogen, such as chloro, fluoro, bromo, and the like-   fluorocarbyl, such as CF₃, CF₂CF₃, etc.;-   phosphorous substituents, such as PO₃ ²⁻, and the like;-   sulfur substituents, including S-hydrocarbyl, SH, SO₃H,    SO₂-hydrocarbyl, SO₃-hydrocarbyl, and the like.

In certain embodiments, the number of non-hydrogen atoms is 6 or less ina substituent. In other embodiments, the number of non-hydrogen atoms is3 or less in a substituent. In other embodiments, the number ofnon-hydrogen atoms on a substituent is 1.

In certain embodiments, the substituents contain only hydrogen, carbon,oxygen, halogen, nitrogen, and sulfur. In other embodiments, thesubstituents contain only hydrogen, carbon, oxygen, and halogen.

Unless otherwise indicated, references to aryl, heteroaryl, phenyl,thienyl, benzothienyl, and the like are intended to mean both thesubstituted and the unsubstituted moiety.

Substituted aryl or heteroaryl may have one or more substituents, up toas many as the ring or ring system will bear, and the substituents maybe the same or different. Thus, for example, an aryl ring or aheteroaryl ring may be substituted with chloro and methyl; methyl, OH,and F; CN, NO₂, and ethyl; and the like including any conceivablesubstituent or combination of substituent possible in light of thisdisclosure.

Thus, compounds wherein B is any of the above classes or species of arylor heteroaryl are contemplated herein.

Further, while not intending to limit the scope of the invention in anyway, in one embodiment B is phenyl. In another embodiment B ischlorophenyl, meaning phenyl with one or more chloro substituents. Inanother embodiment D is 3,5-dichlorophenyl. In another embodiment B isunsubstituted phenyl. In another embodiment B is alkylphenyl. In anotherembodiment B is t-butylphenyl.

In another embodiment B is not unsubstituted phenyl. In anotherembodiment B is not chlorophenyl. In another embodiment B is notfluorophenyl. In another embodiment B is not dimethylaminophenyl. Inanother embodiment B is not unsubstituted phenyl, chlorophenyl,fluorophenyl, or dimethylaminophenyl.

In another embodiment B is hydroxyalkylphenyl, meaning phenyl with ahydroxyalkyl substitutuent such as Ph-CH(OH)C(CH₃)₃.

B can also be any of the groups shown below, where the remainder of themolecule attaches to the phenyl ring. The names of these moieties areshown to the right of the structure.

One compound comprises

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein a dashed line indicates the presence or absence of a bond-   R is hydrocarbyl or hydroxyhydrocarbyl having from 1 to 12 carbon    atoms.

Another embodiment comprises

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein a dashed line indicates the presence or absence of a bond;-   R³, R⁴, and R⁵ are independently H or C₁₋₆ alkyl.

As the dashed line indicates the presence or absence of a bond, R⁴ andR⁵ may be two separate moieties. For example, while not intending to belimiting, in one embodiment R⁴ and R⁵ is methyl, and no bond is presentwhere indicated by the dashed line.

For example, a compound according to the formula below

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof is contemplated. Alternatively, while not intending to limit    the scope of the invention in any way, R⁴ and R⁵ may form a ring. In    other words, a compound such as the one shown below is possible,    wherein x is from 1 to 6.

-   A pharmaceutically acceptable salt, prodrug, or a metabolite thereof    is also contemplated.

Another embodiment comprises

-   A pharmaceutically acceptable salt, prodrug, or a metabolite thereof    is also contemplated.

Other useful compounds comprise

-   A pharmaceutically acceptable salt, prodrug, or a metabolite thereof    is also contemplated.

Other useful examples of compounds comprise

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof.

Other compounds comprise

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof,-   wherein R⁶ is cycloalkyl comprising from 3 to 10 carbon atoms.

Other compounds comprise

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof,-   wherein R⁷ is linear alkyl comprising from 3 to 7 carbon atoms.

Other compounds comprise

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof,-   wherein X¹ and X² are independently CH, O, or S; and-   R⁷ is linear alkyl comprising from 3 to 7 carbon atoms.

Other compounds comprise

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof.

Other compounds comprise

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof,-   wherein X¹ and X² are independently CH, O, or S.

Other compounds comprise

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof.

Other compounds comprise

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof.

Another useful compound is

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof.

Another useful compound is

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof.

In one embodiment, a compound comprising

-   is not used, wherein-   D is phenyl or cyclohexyl; and-   E is unsubstituted phenyl, chlorophenyl, fluorophenyl, or    dimethylaminophenyl.

Another compound comprises

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—.

Another compound comprises

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—.

Another compound comprises

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein a dashed line indicates the presence or absence of a bond;-   R is hydrocarbyl or hydroxyhydrocarbyl having from 1 to 12 carbon    atoms;-   X is CH₂, O, or S; and-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—.

Another compound is an N-aryl or N-heteroaryl gamma lactam which isactive at a prostaglandin receptor. This compound may or may notincorporate any other structural limitation disclosed herein.

Another compound is an N-aryl or N-heteroaryl gamma lactam which isselectively active at a prostaglandin EP₂ receptor. This compound may ormay not incorporate any other structural limitation disclosed herein.

Another compound is an N-aryl or N-heteroaryl gamma lactam which iseffective at reducing intraocular pressure in a mammal. This compoundmay or may not incorporate any other structural limitation disclosedherein.

The determination of whether a compound is active at a prostaglandinreceptor is well within the ability of a person of ordinary skill in theart. The determination of whether a compound is active at aprostaglandin EP₂ receptor is also well within the ability of a personof ordinary skill in the art. While not intending to limit the scope ofthe invention in any way, one method of making such determinations isalso provided in the examples herein.

The determination of whether a compound is effective at reducingintraocular pressure in a mammal is well within the ability of a personof ordinary skill in the art. While not intending to limit the scope ofthe invention in any way, methods of determining whether a compound iseffective in reducing intraocular pressure are given for a few exemplarymammals herein.

While not intending to limit the scope of the invention in any way,examples of useful compounds are depicted below, and pharmaceuticallyacceptable salts, prodrugs, or metabolites thereof.

In one embodiment A is —S(CH₂)₃S(CH₂)₂— and B is phenyl.

In another embodiment A is —(CH₂)₄—CH₂— and B is phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is phenyl.

As mentioned before, phenyl in the above embodiments means substitutedor unsubstituted phenyl unless indicated otherwise.

In one embodiment A is —S(CH₂)₃S(CH₂)₂— and B is (1-hydroxyhexyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is (1-hydroxyhexyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(1-hydroxyhexyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(1-hydroxyhexyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(1-hydroxyhexyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (1-hydroxyhexyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (1-hydroxyhexyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(1-hydroxyhexyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (1-hydroxyhexyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (1-hydroxyhexyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(hydroxymethyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is (hydroxymethyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(hydroxymethyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(hydroxymethyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(hydroxymethyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (hydroxymethyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (hydroxymethyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(hydroxymethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (hydroxymethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (hydroxymethyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is[(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is[(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is[(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is[(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is[(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is [(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is [(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is[(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is [(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is [(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is t-butylphenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is t-butylphenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B ist-butylphenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is t-butylphenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is t-butylphenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is t-butylphenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is t-butylphenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is t-butylphenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is t-butylphenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is t-butylphenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(cyclohexylhydroxymethyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(cyclohexylmethyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(cyclohexylmethyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(cyclohexylmethyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(cyclohexylmethyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(cyclohexylmethyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (cyclohexylmethyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (cyclohexylmethyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(cyclohexylmethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (cyclohexylmethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (cyclohexylmethyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is indanyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is indanyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is indanyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is indanyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is indanyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is indanyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is indanyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is indanyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is indanyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is indanyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is indanolyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is indanolyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is indanolyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is indanolyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is indanolyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is indanolyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is indanolyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is indanolyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is indanolyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is indanolyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is indanonyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is indanonyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is indanonyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is indanonyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is indanonyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is indanonyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is indanonyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is indanonyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is indanonyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is indanonyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(1-hydroxycyclobutyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(1-hydroxycyclobutyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(1-hydroxycyclobutyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(1-hydroxycyclobutyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(1-hydroxycyclobutyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (1-hydroxycyclobutyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (1-hydroxycyclobutyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(1-hydroxycyclobutyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (1-hydroxycyclobutyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (1-hydroxycyclobutyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (1-hydroxy-2-phenylethyl)phenyl.

Another embodiment comprises a compound selected from the groupconsisting of

-   5-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxy]-pentanoic    acid;-   3-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-benzoic    acid;-   5-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-furan-2-carboxylic    acid;-   5-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylic    acid;-   7-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-yl]-heptanoic    acid;-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl-furan-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-2-methyl-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-2-phenyl-ethyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid; and-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid.

The compounds of disclosed herein are useful for the prevention ortreatment of glaucoma or ocular hypertension in mammals, or for themanufacture of a medicament for the treatment of glaucoma or ocularhypertension. They are also useful for the treatment of those diseasesdisclosed in the art as being amenable to treatment by prostaglandin EP₂agonist, such as the ones listed previously.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions, lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of Cl (i.e.the terminal carboxylic acid of a natural prostaglandin), or an estermay be derived from a carboxylic acid functional group on another partof the molecule, such as on a phenyl ring. While not intending to belimiting, an ester may be an alkyl ester, an aryl ester, or a heteroarylester. The term alkyl has the meaning generally understood by thoseskilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

A metabolite is broadly defined as a compound which is formed in vivofrom the disclosed compound.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distcaratemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administeredis, of course, dependent on the therapeutic effect or effects desired,on the specific mammal being treated, on the severity and nature of themammal's condition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds ispreferably in the range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustorq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The compounds disclosed herein are also useful in combination with otherdrugs useful for the treatment of glaucoma or other conditions.

For the treatment of glaucoma, combination treatment with the followingclasses of drugs are contemplated:

-   β-Blockers (or β-adrenergic antagonists) including carteolol,    levobunolol, metiparanolol, timolol hemihydrate, timolol maleate,    β1-selective antagonists such as betaxolol, and the like, or    pharmaceutically acceptable salts or prodrugs thereof;-   Adrenergic Agonists including-   non-selective adrenergic agonists such as epinephrine borate,    epinephrine hydrochloride, and dipivefrin, and the like, or    pharmaceutically acceptable salts or prodrugs thereof; and-   α₂-selective adrenergic agonists such as apraclonidine, brimonidine,    and the like, or pharmaceutically acceptable salts or prodrugs    thereof;-   Carbonic Anhydrase Inhibitors including acetazolamide,    dichlorphenamide, methazolamide, brinzolamide, dorzolamide, and the    like, or pharmaceutically acceptable salts or prodrugs thereof;-   Cholinergic Agonists including-   direct acting cholinergic agonists such as carbachol, pilocarpine    hydrochloride, pilocarbine nitrate, pilocarpine, and the like, or    pharmaceutically acceptable salts or prodrugs thereof;-   chlolinesterase inhibitors such as demecarium, echothiophate,    physostigmine, and the like, or pharmaceutically acceptable salts or    prodrugs thereof;-   Glutamate Antagonists and other neuroprotective agents such as Ca²⁺    channel blockers such as memantine, amantadine, rimantadine,    nitroglycerin, dextrophan, detromethorphan, CGS-19755,    dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil,    diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related    drugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine,    2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine,    barnidipine, verapamil, lidoflazine, prenylamine lactate, amiloride,    and the like, or pharmaceutically acceptable salts or prodrugs    thereof;-   Prostamides such as bimatoprost, or pharmaceutically acceptable    salts or prodrugs thereof; and-   Prostaglandins including travoprost, UFO-21, chloprostenol,    fluprostenol, 13,14-dihydrochloprostenol, isopropyl unoprostone,    latanoprost and the like.-   Cannabinoids including CB1 agonists such as WIN-55212-2 and CP-55940    and the like, or pharmaceutically acceptable salts or prodrugs    thereof.-   For treatment of diseases affecting the eye including glaucoma,    these compounds can be administered topically, periocularly,    intraocularly, or by any other effective means known in the art.

Treatment of inflammatory bowel disease may be accomplished by theadministration of the compounds described herein to the sufferingmammal. Inflammatory bowel disease describes a variety of diseasescharacterized by inflammation of the bowels including, but not limitedto, ulcerative colitis and Crohn's disease. Treatment may beaccomplished by oral administration, by suppository, or parenteraladministration, or some other suitable method.

While not intending to limit the scope of the invention in any way,delivery of the compounds disclosed herein to the colon via oral dosageforms may be accomplished by any of a number of methods known in theart. For example, reviews by Chourasia and Jain in J Pharm PharmaceutSci 6 (1): 33-66, 2003 and Shareef et. al (AAPS PharmSci 2003; 5 (2)Article 17) describe a number of useful methods. While not intending tolimit the scope of the invention in any way these methods include 1)administration of a prodrug, including an azo or a carbohydrate basedprodrug; 2) coating the drug with, or encapsulating or impregnating thedrug into a polymer designed for delivery to the colon, 3) time releaseddelivery of the drug, 4) use of a bioadhesive system; and the like.

While not intending to be bound in any way by theory, it is believedthat intestinal microflora are capable of reductive cleavage of an azobond leaving the two nitrogen atoms as amine functional groups. Whilenot intending to limit the scope of the invention in any way, the azoprodrug approach has been used to deliver to 5-aminosalicylic acid tothe colons of humans in clinical trials for the treatment ofinflammatory bowel disease. It is also believed that bacteria of thelower GI also have enzymes which can digest glycosides, glucuronides,cyclodextrins, dextrans, and other carbohydrates, and ester prodrugsformed from these carbohydrates have been shown to deliver the parentactive drugs selectively to the colon. For example, in vivo and in vitrostudies on rats and guinea pigs with prodrugs of dexamethasone,prednisolone, hydrocortisone, and fludrocortisone, suggest thatglycoside conjugates may be useful for the delivery of steroids to thehuman colon. Other in vivo studies have suggested that glucouronide,cyclodextrin, and dextran prodrugs of steroids or non-steroidalanti-inflammatory drugs are useful for delivery of these drugs to thelower GI tract. An amide of salicylic acid and glutamic acid has beenshown to be useful for the delivery of salicylic acid to the colon ofrabbit and dog.

While not intending to limit the scope of the invention in any way,carbohydrate polymers such as amylase, arabinogalactan, chitosan,chondroiton sulfate, dextran, guar gum, pectin, xylin, and the like, orazo-group containing polymers can be used to coat a drug compound, or adrug may be impregnated or encapsulated in the polymer. It is believedthat after oral administration, the polymers remain stable in the upperGI tract, but are digested by the microflora of the lower GI thusreleasing the drug for treatment.

Polymers which are sensitive to pH may also be used since the colon hasa higher pH than the upper GI tract. Such polymers are commerciallyavailable. For example, Rohm Pharmaceuticals, Darmstadt, Germany,markets pH dependent methacrylate based polymers and copolymers whichhave varying solubilities over different pH ranges based upon the numberof free carboxylate groups in the polymer under the tradename Eudragit®.Several Eudragit® dosage forms are currently used to deliver salsalazinefor the treatment of ulcerative colitis and Crohn's disease. Timerelease systems, bioadhesive systems, and other delivery systems havealso been studied.

One embodiment is use of a compound in the manufacture of a medicamentfor the treatment of inflammatory bowel disease, said compoundcomprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is aryl or heteroaryl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is phenyl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is alkylphenyl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is p-t-butylphenyl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound of claim selected from the group consisting of

-   5-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxy]-pentanoic    acid;-   3-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-benzoic    acid;-   5-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-furan-2-carboxylic    acid;-   5-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylic    acid;

7-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-yl]-heptanoic acid;

-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-2-methyl-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-2-phenyl-ethyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester;-   3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-benzoic    acid;-   5-{(R)-1-[4-(1-Hydroxy-pentyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-butyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-((E and    Z)-3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-allyl)-thiophene-2-carboxylic    acid;-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid;-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (mixture of diastereomers);-   5-{3-[(S)-1-(4-Hexanoyl-phenyl)-5-oxo-pyrrolidin-2-yl]-propyl}-thiophene-2-carboxylic    acid;-   5-[(R)-1-(4-Hexanoyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (faster eluting diastereomer);-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (slower eluting diastereomer);-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (faster eluting diastereomer);-   5-(3-{(S)-1-[4-(1-hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (slower eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from faster eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from slower eluting diastereomer);-   5-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (mixture of diastereomers);-   5-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (faster eluting diastereomer);-   5-{(R)-1-[4-(1-hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (slower eluting diastereomer);-   5-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid;-   5-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (faster eluting diastereomer);-   5-(3-{(S)-1-[4-(1-hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (slower eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from faster eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from slower eluting diastereomer); and-   4-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxy}-benzoic    acid.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound of comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—; and-   B is aryl or heteroaryl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound of comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—; and-   B is phenyl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound of comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—; and-   B is hydroxyalkylphenyl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein a dashed line indicates the presence or absence of a bond;-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   R is hydrocarbyl or hydroxyhydrocarbyl having from 1 to 12 carbon    atoms;-   X is CH₂, O, or S; and-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound comprising an N-aryl or N-heteroaryl gamma lactam which iseffective at reducing intraocular pressure in a mammal.

One embodiment is a compound comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is aryl or heteroaryl.

Another embodiment is a compound comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be substituted with S or O; or A is—(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is from 1 to 4, and wherein oneCH₂ may be substituted with S or O; and

-   B is phenyl.

Another embodiment is a compound comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is alkylphenyl.

Another embodiment is a compound comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is p-t-butylphenyl.

Another embodiment is a compound of claim selected from the groupconsisting of

-   5-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxy]-pentanoic    acid;-   3-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-benzoic    acid;-   5-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-furan-2-carboxylic    acid;-   5-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylic    acid;-   7-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-yl]-heptanoic    acid;-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-2-methyl-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-2-phenyl-ethyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester;-   3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-benzoic    acid;-   5-{(R)-1-[4-(1-Hydroxy-pentyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-butyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-((E and    Z)-3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-allyl)-thiophene-2-carboxylic    acid;-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid;-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (mixture of diastereomers);-   5-{3-[(S)-1-(4-Hexanoyl-phenyl)-5-oxo-pyrrolidin-2-yl]-propyl}-thiophene-2-carboxylic    acid;-   5-[(R)-1-(4-Hexanoyl-phenyl)-5-oxo-pyrrolidin-2-yl]methoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (faster eluting diastereomer);-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (slower eluting diastereomer);-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (faster eluting diastereomer);-   5-(3-{(S)-1-[4-(1-hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (slower eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from faster eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from slower eluting diastereomer);-   5-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (mixture of diastereomers);-   5-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (faster eluting diastereomer);-   5-{(R)-1-[4-(1-hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (slower eluting diastereomer);-   5-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid;-   5-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (faster eluting diastereomer);-   5-(3-{(S)-1-[4-(1-hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (slower eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from faster eluting diastereomer);-   5-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from slower eluting diastereomer); and-   4-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxy}-benzoic    acid. Another embodiment is a compound of comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—; and-   B is aryl or heteroaryl.

Another embodiment is a compound of comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—; and-   B is phenyl.

Another embodiment is a compound of comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—; and-   B is hydroxyalkylphenyl.

Another embodiment is a compound comprising

-   or a pharmaceutically acceptable salt, prodrug, or a metabolite    thereof;-   wherein a dashed line indicates the presence or absence of a bond;-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   R is hydrocarbyl or hydroxyhydrocarbyl having from 1 to 12 carbon    atoms;-   X is CH₂, O, or S; and-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—.

Another embodiment is a compound comprising an N-aryl or N-heteroarylgamma lactam which is effective at reducing intraocular pressure in amammal.

Embodiments contemplated for each compound disclosed herein are use ofthe compound in the manufacture of a medicament for the treatment ofglaucoma or ocular hypertension.

Embodiments contemplated for each compound disclosed herein are use ofthe compound in the manufacture of a medicament for the treatment ofinflammatory bowel disease.

Embodiments contemplated for each compound disclosed herein are methodscomprising administering an effective amount of the compound to a mammalfor the treatment of glaucoma or ocular hypertension.

Embodiments contemplated for each compound disclosed herein are methodscomprising administering an effective amount of the compound to a mammalfor the treatment of inflammatory bowel disease.

Embodiments contemplated for each compound disclosed herein arecompositions comprising the compound, wherein said compositions areophthalmically acceptable liquids.

EXAMPLE 15-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxy]-pentanoicacid (4)

Step 1. Arylation of 1 to Give 2

A solution of amide 1 (3.30 g, 14.4 mmol) in 1,4-dioxane (25 mL) wasadded to a mixture of 4,5-bis(triphenylphosphino)-9,9-dimethylxanthene(xantphos, 600 mg, 1.04 mmol), Pd₂(dba)₃ (317 mg, 0.35 mmol) and Cs₂CO₃(6.46 g, 19.8 mmol). 1-Bromo-4-tert-butylbenzene (2.40 mL, 13.8 mmol)was added and the reaction mixture was purged with nitrogen. The mixturewas heated at reflux for 19 h, then cooled to rt. The reaction mixturewas then filtered through celite, washing with CH₂Cl₂, and the filtratewas concentrated in vacuo. Purification of the residue by flash columnchromatography on silica gel (10%→20% EtOAc/Hexane, gradient) afforded3.53 g (71%) of the desired product 2.

Step 2. Deprotection of 2 to Give 3

HF-pyridine (5 mL) was added to a solution of silyl ether 2 (3.53 g,9.76 mmol) in MeCN (20 mL) in a plastic bottle. The reaction was stirredat rt for 5 h, then was quenched with saturated aqueous NaHCO₃ (250 mL).The mixture was extracted with EtOAc (3×100 mL). The combined extractswere washed with brine (150 mL) then dried (Na₂SO₄), filtered andconcentrated in vacuo to yield 2.14 g (89%) of the desired product 3.

Step 3. Alkylation of 3 to Give the Ester of 4

Sodium hydride (11 mg, 0.46 mmol) was added to a solution of alcohol 3(100 mg, 0.40 mmol) in THF (3 mL) at 0° C. under nitrogen. After 1 h at0° C., methyl 5-bromovalerate (67 μL, 0.47 mmol) was added and thereaction was allowed to warm to rt. After 3 h, tlc analysis showedmostly starting alcohol remaining and another portion of bromide (67 μL,0.47 mmol) was added. After 22 h total reaction time, the reaction wasquenched with 1 N HCl and extracted with EtOAc (3×25 mL). Combinedextracts were dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(40% EtOAc/Hexane→EtOAc, gradient) afforded 19 mg (13%) of the desiredester.

Step 4. Saponification to Give 4

Aqueous lithium hydroxide (1 N, 0.5 mL) was added to a solution of esterfrom step 3 above (12.3 mg, 0.034 mmol) in THF (0.7 mL). After 2.5 h atrt, the reaction was acidified with 0.25 M HCl (5 mL) then extractedwith CH₂Cl₂ (3×7 mL). Combined extracts were dried (Na₂SO₄), filteredand concentrated in vacuo to afford 10.2 mg (86%) of the title compound(4).

EXAMPLE 23-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-benzoicacid (5)

Step 1. Alkylation of 3 to Give the Ester of 5

Potassium hydride (23.4 mg, 0.58 mmol) and 18-crown-6 (167 mg, 0.63mmol) were added sequentially to a solution of alcohol 3 (130 mg, 0.53mmol) in THF (3 mL) at 0° C. After 1 h at 0° C., a solution of methyl3-(chloromethyl)benzoate (prepared from the corresponding acid chloride,pyridine and methanol: see J. Org. Chem. 1988, 53, 2548-2552; 116 mg,0.63 mmol) in THF (1.5 mL) was added via cannula and the reaction wasallowed to warm to rt. After 22.5 h, the reaction was quenched with 0.1N HCl (10 mL) and extracted with EtOAc (3×15 mL). Combined extracts werewashed with saturated aqueous NaHCO₃ (15 mL) and brine (15 mL) thendried (Na₂SO₄), filtered and concentrated in vacuo. Purification of theresidue by flash column chromatography on silica gel (30%→50%EtOAc/Hexane, gradient) afforded 66 mg (32%) of the desired ester.

Step 2. Saponification to Give 5

Aqueous lithium hydroxide (1 N, 0.4 mL) was added to a solution of esterfrom step 1 above (33.5 mg, 0.085 mmol) in THF (0.75 mL). After 3.5 h atrt, the reaction was acidified with 0.25 M HCl (5 mL) then extractedwith CH₂Cl₂ (3×10 mL). Combined extracts were dried (Na₂SO₄), filteredand concentrated in vacuo. Purification of the residue by flash columnchromatography on silica gel (2% MeOH/CH₂Cl₂), followed by preparativethin layer chromatography (10% MeOH/CH₂Cl₂) afforded 6.6 mg (20%) of thetitle compound (5).

EXAMPLE 35-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-furan-2-carboxylicacid (6)

Step 1. Alkylation of 3 to Give the Ester of 6

Potassium hydride (27 mg, 0.67 mmol) and 18-crown-6 (193 mg, 0.73 mmol)were added sequentially to a solution of alcohol 3 (150 mg, 0.61 mmol)in THF (4 mL) at 0° C. After 1 h at 0° C., a solution of ethyl5-chloromethylfuran-2-carboxylate (commercially available from AldrichChemical Company, 138 mg, 0.73 mmol) in THF (1 mL) was added via cannulaand the reaction was allowed to warm to rt. After 18.5 h, the reactionwas quenched with 0.25 N HCl (10 mL) and extracted with EtOAc (3×15 mL).Combined extracts were washed with brine (20 mL) then dried (Na₂SO₄),filtered and concentrated in vacuo. Purification of the residue by flashcolumn chromatography on silica gel (20%→50% EtOAc/Hexane, gradient)afforded 78 mg (32%) of the desired ester.

Step 2. Saponification to Give 6

Aqueous lithium hydroxide (1 N, 0.5 mL) was added to a solution of esterfrom step 1 above (66.7 mg, 0.17 mmol) in THF (0.5 mL). After 3 h at rt,the reaction was acidified with 1 N HCl (2 mL) then extracted withCH₂Cl₂ (3×10 mL). Combined extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo to afford 54.4 mg (88%) of the title compound (6).

EXAMPLE 45-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylicacid (7)

Step 1. Alkylation of 3 to Give the Ester of 7

Potassium hydride (25.2 mg, 0.63 mmol) and 18-crown-6 (181 mg, 0.68mmol) were added sequentially to a solution of alcohol 3 (140 mg, 0.57mmol) in THF (4 mL) at 0° C. After 1.5 h at 0° C., a solution of methyl5-chloromethylthiophene-2-carboxylate (prepared according to theprocedures described in WO2004/037808; 130 mg, 0.68 mmol) in THF (1.5mL) was added via cannula and the reaction was allowed to warm to rt.After 20 h, the reaction was quenched with 0.25 N HCl (15 mL) andextracted with EtOAc (3×20 mL). Combined extracts were washed with brine(30 mL) then dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(20%→50% EtOAc/Hexane, gradient) afforded 40.7 mg (18%) of the desiredester.

Step 2. Saponification to Give 7

Aqueous lithium hydroxide (1 N, 0.4 mL) was added to a solution of esterfrom step 1 above (37 mg, 0.092 mmol) in THF (0.75 mL). After 18 h atrt, the reaction was acidified with 1 N HCl (7 mL) then extracted withCH₂Cl₂ (3×10 mL). Combined extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo to afford 22.3 mg (62%) of the title compound (7).

EXAMPLE 57-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-yl]-heptanoic acid(10)

Step 1. Oxidation of 3 to Give Aldehyde 8

Molecular sieves (4 Å, 300 mg), 4-methylmorpholine N-oxide (427 mg, 3.64mmol) and tetrapropylammonium perruthenate (250 mg, 0.71 mmol) wereadded sequentially to a solution of alcohol 3 (600 mg, 2.43 mmol) inCH₂Cl₂ (15 mL) at rt. After 23 h, the reaction mixture was filteredthrough celite, washing with CH₂Cl₂ (10 mL). The filtrate wasconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica gel (CH₂Cl₂→10% EtOAc/CH₂Cl₂, gradient)afforded 92 mg (15%) of the desired aldehyde 8.

Step 2. Wittig Reaction of 8 to Give 9

Potassium bis(trimethylsilyl)amide (0.5 M in PhMe, 1.92 mL, 0.96 mmol)was added to a solution of aldehyde 8 (86 mg, 0.35 mmol) in THF (2 mL)at rt. After 15 min at rt, the reaction mixture was cooled to −55° C.for 10 min before a solution of 5-carboxypentyltriphenylphosphoniumbromide (207 mg, 0.45 mmol) was added via cannula. After 10 min at −55°C., the reaction was allowed to warm to rt. After 18 h at rt, thereaction was quenched with saturated aqueous NH₄Cl (15 mL) and extractedwith EtOAc (3×15 mL). Combined extracts were washed with brine (20 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. Purification of theresidue by preparative thin layer chromatography (5% MeOH/CH₂Cl₂)afforded 10.5 mg (9%) of desired alkene 9.

Step 3. Hydrogenation of 9 to Give 10

Palladium on carbon (10 wt. %, 2 mg) was added to a solution of alkene 9(5.8 mg, 0.017 mmol) in MeOH (1 mL). A hydrogen atmosphere wasestablished by evacuating and refilling with hydrogen (3×) and thereaction mixture was stirred under a balloon of hydrogen for 18 h. Thereaction mixture was filtered through celite, washing with MeOH, and thefiltrate was concentrated in vacuo to afford 4.1 mg (70%) of the titlecompound (10).

EXAMPLE 65-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylicacid (17)

Step 1. Arylation of 1 to Give 12

A solution of amide 1 (2.89 g, 12.60 mmol) in 1,4-dioxane (20 mL)followed by a solution of 1-(4-methoxybenzyloxymethyl)-4-bromobenzene(11: for synthesis, see Allergan docket #17693; 3.88 g, 12.63 mmol) wereadded sequentially to a mixture of xantphos (877 mg, 1.52 mmol),Pd₂(dba)₃ (463 mg, 0.51 mmol) and Cs₂CO₃ (3.2 g, 9.82 mmol) via cannula.The reaction mixture was purged with nitrogen and then heated at refluxfor 22 h. The reaction mixture was allowed to cool to rt then filteredthrough celite, washing with CH₂Cl₂, and the filtrate was concentratedin vacuo. Purification of the residue by flash column chromatography onsilica gel (5%→25% EtOAc/Hexane, gradient) afforded 1.70 g (30%) ofdesired product 12.

Step 2. Deprotection of 12 to Give 13

HF-pyridine (5 mL) was added to a solution of silyl ether 12 (1.38 g,3.03 mmol) in MeCN (15 mL) in a plastic bottle at 0° C. The reaction wasstirred at 0° C. for 3 h, then was quenched with saturated aqueousNaHCO₃ (250 mL). The mixture was extracted with EtOAc (3×100 mL). Thecombined extracts were washed with brine (100 mL) then dried (Na₂SO₄),filtered and concentrated in vacuo. Purification of the residue by flashcolumn chromatography on silica gel (1%→3% MeOH/CH₂Cl₂, gradient)afforded 464 mg (45%) of desired alcohol 13.

Step 3. Alkylation of Alcohol 13 to Give 14

Potassium hydride (44 mg, 1.10 mmol) and 18-crown-6 (365 mg, 1.38 mmol)were added sequentially to a solution of alcohol 13 (315 mg, 0.92 mmol)in THF (4 mL) at 0° C. After 1 h at 0° C., ethyl5-chloromethylfuran-2-carboxylate (0.28 mL, 1.82 mmol) was added and thereaction was allowed to warm to rt. After 22 h, the reaction wasquenched with 0.5 N HCl (20 mL) and extracted with EtOAc (3×25 mL).Combined extracts were washed with brine (50 mL) then dried (Na₂SO₄),filtered and concentrated in vacuo. Purification of the residue by flashcolumn chromatography on silica gel (20% EtOAc/Hexane→EtOAc, gradient)afforded 148 mg (32%) of desired product 14.

Step 4. Oxidative Deprotection of 14 to Give 15 and 16

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 82 mg, 0.36 mmol) wasadded to a mixture of 14 (143 mg, 0.29 mmol) in CH₂Cl₂ (4 mL) and water(0.2 mL). After 3 h, tlc indicated that starting material remained andanother portion of DDQ (82 mg, 0.36 mmol) was added. After a further1.25 h, the reaction was quenched with saturated aqueous NaHCO₃ (20 mL).The mixture was extracted with EtOAc (3×20 mL). The combined extractswere washed with brine (20 mL) then dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica gel (CH₂Cl₂→3% MeOH/CH₂Cl₂, gradient) afforded38 mg (35%) of the desired alcohol 15 and 61 mg of impure aldehyde 16.Aldehyde 16 was further purified by preparative thin layerchromatography (5% MeOH/CH₂Cl₂) to afford 48.7 mg (45%) of aldehyde 16.

Step 5. Oxidation of 15 to Give 16

Molecular sieves (4 Å, 3 mg), 4-methylmorpholine N-oxide (12.6 mg, 0.11mmol) and tetrapropylammonium perruthenate (2.5 mg, 0.007 mmol) wereadded sequentially to a solution of alcohol 15 (26.8 mg, 0.072 mmol) inCH₂Cl₂ (1.5 mL) at rt. After 20 min, the reaction mixture was filteredthrough celite, washing with CH₂Cl₂ (5 mL). The filtrate wasconcentrated in vacuo. Purification of the residue by preparative thinlayer chromatography (5% MeOH/CH₂Cl₂) afforded 9.6 mg (36%) of thedesired aldehyde 16.

Step 6. Grignard Reaction with 16 to Give the Ester of 17

Pentyl magnesium bromide (2.0 M in Et₂O, 32 μL, 0.064 mmol) was added toa solution of aldehyde 16 (21.7 mg, 0.058 mmol) in THF (0.4 mL) at −40°C. under nitrogen. After 25 min, the reaction was quenched withsaturated aqueous NH₄Cl and extracted with CH₂Cl₂ (3×7 mL). Combinedextracts were dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by preparative thin layer chromatography (5%MeOH/CH₂Cl₂) afforded 10.6 mg (41%) of the desired ester.

Step 7. Saponification to Give 17

Aqueous lithium hydroxide (1 N, 0.1 mL) was added to a solution of esterfrom step 6 above (8.8 mg, 0.02 mmol) in THF (0.2 mL). After 1 h at rt,the reaction was acidified with 0.5 N HCl (1 mL) then extracted withCH₂Cl₂ (3×7 mL). Combined extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo to afford 8.2 mg (99%) of the title compound (17).

EXAMPLE 75-{(R)-1-[4-(1-Hydroxy-2-methyl-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylicacid (18)

Step 1. Grignard Reaction with 16 to Give the Ester of 18

Isopropyl magnesium chloride (2.0 M in THF, 31 μL, 0.062 mmol) was addedto a solution of aldehyde 16 (20.5 mg, 0.055 mmol) in THF (0.4 mL) at−40° C. under nitrogen. After 35 min, the reaction was quenched withsaturated aqueous NH₄Cl and extracted with CH₂Cl₂ (3×7 mL). Combinedextracts were dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by preparative thin layer chromatography (5%MeOH/CH₂Cl₂) afforded 5 mg (22%) of the desired ester.

Step 2. Saponification to Give 18

Aqueous lithium hydroxide (1 N, 0.05 mL) was added to a solution of theester from step 1 above (3.1 mg, 0.007 mmol) in THF (0.15 mL). After 1 hat rt, the reaction was acidified with 0.2 N HCl (1 mL) then extractedwith CH₂Cl₂ (3×7 mL). Combined extracts were dried (Na₂SO₄), filteredand concentrated in vacuo to afford 2.5 mg (86%) of the title compound(18).

EXAMPLE 85-{(R)-1-[4-(1-Hydroxy-2-phenyl-ethyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylicacid (19)

Step 1. Grignard Reaction with 16 to Give the Ester of 19

Benzyl magnesium chloride (2.0 M in THF, 14 μL, 0.028 mmol) was added toa solution of aldehyde 16 (9.6 mg, 0.026 mmol) in THF (0.3 mL) at −40°C. under nitrogen. After 45 min, the reaction was warmed to 0° C. After25 min at 0° C., the reaction was quenched with saturated aqueous NH₄C1and extracted with CH₂Cl₂ (3×7 mL). Combined extracts were dried(Na₂SO₄), filtered and concentrated in vacuo. Purification of theresidue by preparative thin layer chromatography (7% MeOH/CH₂Cl₂)afforded 3.3 mg (28%) of the desired ester.

Step 2. Saponification to Give 19

Aqueous lithium hydroxide (1 N, 0.05 mL) was added to a solution of theester from step 1 above (2.4 mg, 0.005 mmol) in THF (0.15 mL). After 2.5h at rt, the reaction was acidified with 0.2 N HCl (1 mL) then extractedwith CH₂Cl₂ (3×7 mL). Combined extracts were dried (Na₂SO₄), filteredand concentrated in vacuo to afford 2.2 mg (98%) of the title compound(19)

EXAMPLE 95-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid (23)

Step 1. Alkylation of 13 to Give 20

Potassium hydride (55.5 mg, 1.38 mmol) and 18-crown-6 (456 mg, 1.73mmol) were added sequentially to a solution of alcohol 13 (394 mg, 1.15mmol) in THF (5 mL) at 0° C. After 1 h at 0° C., a solution of methyl5-chloromethylthiophene-2-carboxylate (439 mg, 2.30 mmol) in THF (2 mL)was added via cannula and the reaction was allowed to warm to rt. After19 h, tlc analysis showed starting material remained. Another portion ofKH (20 mg, 0.50 mmol) was added and the reaction was heated at 50° C.After 2 h at 50° C., the reaction was cooled and quenched with 0.5 N HCl(20 mL) and extracted with EtOAc (3×25 mL). Combined extracts werewashed with brine (50 mL) then dried (Na₂SO₄), filtered and concentratedin vacuo. Purification of the residue by flash column chromatography onsilica gel (15% EtOAc/Hexane EtOAc, gradient) afforded 108 mg (19%) ofdesired product 20.

Step 2. Oxidative Deprotection of 20 to Give 21 and 22

DDQ (91 mg, 0.40 mmol) was added to a mixture of 20 (98 mg, 0.20 mmol)in CH₂Cl₂ (3 mL) and water (0.15 mL). After 4.5 h, the reaction wasquenched with saturated aqueous NaHCO₃ (15 mL) and extracted with EtOAc(3×25 mL). Combined extracts were washed with brine (40 mL) then dried(Na₂SO₄), filtered and concentrated in vacuo. Purification of theresidue by preparative thin layer chromatography (5% MeOH/CH₂Cl₂)afforded 14.4 mg (19%) of alcohol 21 and 16.2 mg (22%) of aldehyde 22.

Step 3. Grignard Reaction with 22 to Give the Ester of 23

Pentyl magnesium bromide (2.0 M in Et₂O, 22 μL, 0.044 mmol) was added toa solution of aldehyde 22 (11 mg, 0.029 mmol) in THF (0.2 mL) at −40° C.under nitrogen. After 1.5 h, the reaction was quenched with saturatedaqueous NH₄Cl and extracted with CH₂Cl₂ (3×7 mL). Combined extracts weredried (Na₂SO₄), filtered and concentrated in vacuo. Purification of theresidue by preparative thin layer chromatography (5% MeOH/CH₂Cl₂)afforded 4.8 mg (37%) of the desired ester.

Step 4. Saponification to Give 23

Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution ofthe ester from step 3 above (3.6 mg, 0.008 mmol) in MeCN (0.1 mL) and pH7.2 buffer (2.5 mL). After 16.5 h at rt, the reaction was diluted withMeCN (7 mL) and concentrated in vacuo. The residue was suspended inCH₂Cl₂ and filtered through a cotton plug. The filtrate was concentratedin vacuo to afford 2.0 mg (57%) of the title compound (23).

EXAMPLE 105-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid isopropyl ester (28)

Step 1. Arylation of 1 to Give 24

A solution of amide 1 (3.37 g, 14.7 mmol) in 1,4-dioxane (30 mL) wasadded to a mixture of Pd₂(dba)₃ (540 mg, 0.59 mmol), xantphos (1.02 g,1.76 mmol) and Cs₂CO₃ (5.74 g, 17.6 mmol). A solution of1-(1-(4-methoxybenzyloxyhexyl)-4-bromobenzene (preparation 1, 4.99 g,13.22 mmol) in 1,4-dioxane (30 mL) was added via cannula, followed by anadditional 40 mL of 1,4-dioxane. The reaction mixture was purged withnitrogen then heated at reflux overnight. After 20 h, the reaction wascooled to rt and filtered through celite, washing with CH₂Cl₂. Thefiltrate was concentrated in vacuo and the residue was purified by flashcolumn chromatography on silica gel (5%→30% EtOAc/Hexane, gradient) toafford 5.79 g (83%) of the desired product 24.

Step 2. Deprotection of 24 to Give 25

HF-pyridine (7 mL) was added to a solution of silyl ether 24 (4.05 g,7.72 mmol) in MeCN (40 mL) in a plastic bottle at 0° C. The reaction wasstirred at 0° C. for 1 h, then was quenched with saturated aqueousNaHCO₃ (300 mL). The mixture was extracted with EtOAc (3×150 mL). Thecombined extracts were washed with brine (200 mL) then dried (Na₂SO₄),filtered and concentrated in vacuo. Purification of the residue by flashcolumn chromatography on silica (CH₂Cl₂→3% MeOH/CH₂Cl₂, gradient)afforded 2.3 g (72%) of the desired alcohol 25.

Step 3. Alkylation of 25 to Give 26

Potassium hydride (155 mg, 3.86 mmol) was added to a solution of alcohol25 (1.22 g, 2.97 mmol) in THF (7 mL) at 0° C. After 15 min at 0° C.,18-crown-6 (1.02 g, 3.86 mmol) was added. After 45 min longer at 0° C.,a solution of isopropyl 5-chloromethylthiophene-2-carboxylate(preparation 2, 650 mg, 2.97 mmol) in THF (5 mL) was added via cannula.Potassium iodide (50 mg, 0.30 mmol) was added and the reaction wasallowed to warm to rt. After 20 h, the reaction was quenched with 0.5 NHCl (70 mL) and extracted with EtOAc (3×100 mL). Combined extracts werewashed with brine (100 mL) then dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica gel (20% EtOAc/Hexane→EtOAc, gradient) afforded296 mg (17%) of desired product 26 along with 747 mg (61%) of recoveredstarting alcohol 25.

Step 4. Oxidative Deprotection of 26 to Give 27 and 28

DDQ (93 mg, 0.41 mmol) was added to a solution of 26 (220 mg, 0.37 mmol)in CH₂Cl₂ (4 mL) and water (0.2 mL) at 0° C. under nitrogen. After 35min, the reaction was quenched with saturated aqueous NaHCO₃ (30 mL) andextracted with EtOAc (3×30 mL). Combined extracts were washed with brine(50 mL) then dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(20%→70% EtOAc/Hexane, gradient) afforded 13 mg (7%) of ketone 27 and108 mg (62%) of the title compound (28).

EXAMPLE 113-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-benzoicacid (31)

Step 1. Alkylation of 13 to Give 29

Potassium hydride (16 mg, 0.39 mmol) was added to a solution of alcohol13 (112 mg, 0.33 mmol) in THF (1.0 mL) at 0° C. After 1 h at 0° C.,18-crown-6 (114 mg, 0.43 mmol), potassium iodide (5 mg, 0.03 mmol) and asolution of methyl 3-chloromethylbenzoate (121 mg, 0.66 mmol) in THF(0.5 mL) were added sequentially. The reaction was allowed to warm tort. After 19 h, the reaction was quenched with 0.1 N HCl (10 mL) andextracted with EtOAc (3×10 mL). Combined extracts were washed with brine(15 mL) then dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(20% EtOAc/Hexane→EtOAc, gradient) afforded 23 mg (14%) of desiredproduct 29.

Step 2. Oxidative Deprotection of 29 to Give 30

DDQ (23 mg, 0.10 mmol) was added to a mixture of 29 (23 mg, 0.047 mmol)in CH₂Cl₂ and water (20:1, 0.25 mL). After 3.75 h, the reaction wasquenched with saturated aqueous NaHCO₃ (10 mL) and extracted with EtOAc(3×7 mL). Combined extracts were washed with brine (10 mL) then dried(Na₂SO₄), filtered and concentrated in vacuo. Purification of theresidue by preparative thin layer chromatography (80% EtOAc/Hex)afforded 13 mg (58%) of aldehyde 30.

Step 3. Grignard Reaction with 30 to Give the Ester of 31

Pentyl magnesium bromide (2.0 M in Et₂O, 50 μL, 0.10 mmol) was added toa solution of aldehyde 30 (12.4 mg, 0.034 mmol) in THF (0.1 mL) at −40°C. under nitrogen. After 1 h, the reaction was quenched with saturatedaqueous NH₄Cl (7 mL) and extracted with CH₂Cl₂ (3×7 mL). Combinedextracts were dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by preparative thin layer chromatography (5%MeOH/CH₂Cl₂) afforded 8.6 mg (58%) of the desired ester.

Step 4. Saponification to Give 31

Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution ofthe ester from step 3 above (7.4 mg, 0.017 mmol) in MeCN (0.1 mL) and pH7.2 buffer (2.5 mL). After 18 h at rt, the reaction was diluted withMeCN (7 mL) and concentrated in vacuo. Purification of the residue bypreparative thin layer chromatography (5% MeOH/CH₂Cl₂) afforded 1.5 mg(21%) of the title compound (31).

EXAMPLE 125-{(R)-1-[4-(1-Hydroxy-pentyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid (32)

Step 1. Grignard reaction with 22 to give the ester of 32

n-Butyl magnesium chloride (2.0 M in THF, 41 μL, 0.082 mmol) was addedto a solution of aldehyde 22 (20.2 mg, 0.054 mmol) in THF (0.1 mL) at−40° C. under nitrogen. After 1 h, the reaction was quenched withsaturated aqueous NH₄Cl (10 mL) and extracted with CH₂Cl₂ (3×7 mL).Combined extracts were dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the residue by preparative thin layerchromatography (5% MeOH/CH₂Cl₂) afforded 12.3 mg (53%) of the desiredester.

Step 2. Saponification to Give 32

Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution ofthe ester from step 1 above (11.2 mg, 0.026 mmol) in MeCN (0.1 mL) andpH 7.2 buffer (3.0 mL). After 19 h at rt, the reaction was diluted withMeCN (10 mL) and concentrated in vacuo. The residue was suspended in 5%MeOH/CH₂Cl₂ and filtered through a cotton plug. The filtrate wasconcentrated in vacuo to afford 10.7 mg (99%) of the title compound(32).

EXAMPLE 135-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid (33)

Step 1. Grignard Reaction with 22 to Give the Ester of 33

n-Hexyl magnesium bromide (2.0 M in Et₂O, 100 μL, 0.20 mmol) was addedto a solution of aldehyde 22 (24.6 mg, 0.054 mmol) in THF (0.12 mL) at−40° C. under nitrogen. After 1.5 h, the reaction was quenched withsaturated aqueous NH₄Cl (10 mL) and extracted with CH₂Cl₂ (3×7 mL).Combined extracts were dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the residue by preparative thin layerchromatography (5% MeOH/CH₂Cl₂) afforded 16.3 mg (54%) of the desiredester.

Step 2. Saponification to Give 33

Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution ofthe ester from step 1 above (13 mg, 0.028 mmol) in MeCN (0.1 mL) and pH7.2 buffer (3.0 mL). After 18 h at rt, the reaction was diluted withMeCN (10 mL) and concentrated in vacuo. The residue was suspended in 5%MeOH/CH₂Cl₂and filtered through a cotton plug. The filtrate wasconcentrated in vacuo to afford 11 mg (87%) of the title compound (33).

EXAMPLE 145-{(R)-1-[4-(1-Hydroxy-butyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid (34)

Step 1. Grignard Reaction with 22 to Give the Ester of 34

n-Propyl magnesium chloride (2.0 M in Et₂O, 92 μL, 0.18 mmol) was addedto a solution of aldehyde 22 (22.9 mg, 0.061 mmol) in THF (0.12 mL) at−40° C. under nitrogen. After 1.75 h, the reaction was quenched withsaturated aqueous NH₄Cl (10 mL) and extracted with CH₂Cl₂ (3×7 mL).Combined extracts were dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the residue by preparative thin layerchromatography (5% MeOH/CH₂Cl₂) afforded 13 mg (51%) of the desiredester.

Step 2. Saponification to Give 34

Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution ofthe ester from step 1 above (10.8 mg, 0.026 mmol) in MeCN (0.1 mL) andpH 7.2 buffer (3.0 mL). After 17 h at rt, the reaction was diluted withMeCN (10 mL) and concentrated in vacuo. The residue was suspended in 5%MeOH/CH₂Cl₂and filtered through a cotton plug. The filtrate wasconcentrated in vacuo to afford 10.4 mg (99%) of the title compound(34).

EXAMPLE 155-{(R)-1-[4-(1-Hydroxy-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid (35)

Step 1. Grignard Reaction with 22 to Give the Ester of 35

Ethyl magnesium chloride (2.0 M in Et₂O, 24 μL, 0.048 mmol) was added toa solution of aldehyde 22 (5.8 mg, 0.016 mmol) in THF (0.1 mL) at −40°C. under nitrogen. After 1.25 h, the reaction was quenched withsaturated aqueous NH₄Cl (5 mL) and extracted with CH₂Cl₂ (3×5 mL).Combined extracts were dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the residue by preparative thin layerchromatography (5% MeOH/CH₂Cl₂) afforded 2.5 mg (40%) of the desiredester.

Step 2. Saponification to Give 35

Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution ofthe ester from step 1 above (2.8 mg, 0.007 mmol) in MeCN (0.1 mL) and pH7.2 buffer (2.5 mL). After 17 h at rt, the reaction was diluted withMeCN (10 mL) and concentrated in vacuo. The residue was suspended in 5%MeOH/CH₂Cl₂and filtered through a cotton plug. The filtrate wasconcentrated in vacuo to afford 2.7 mg (99%) of the title compound (35).

EXAMPLE 16 5-((E andZ)-3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-allyl)-thiophene-2-carboxylicacid (41)

Step 1. Oxidation of 25 to Give Aldehyde 36

Dess-Martin periodinane (1.63 g, 3.83 mmol) was added to a solution ofalcohol 25 (1.43 g, 3.48 mmol) in CH₂Cl₂ (12 mL) at rt under nitrogen.After 1 h at rt the reaction was quenched with saturated aqueous NaHCO₃and saturated aqueous NaHSO₃ (1:1, 100 mL). The mixture was extractedwith CH₂Cl₂ (3×150 mL). The combined extracts were dried (Na₂SO₄),filtered and concentrated in vacuo. Purification of the residue by flashcolumn chromatography on silica (2% MeOH/CH₂Cl₂) afforded 915 mg (64%)of the desired aldehyde 36.

Step 2. Methylenation of 36 to Give Alkene 37

The Tebbe reagent (0.5 M in THF, 4.86 mL, 2.43 mmol) was added to asolution of aldehyde 36 (677 mg, 1.65 mmol) in THF (11 mL) at −40° C.under nitrogen. After 1 h at −40° C. the reaction was quenched byaddition of aqueous 2 N NaOH (1.65 mL) and stirred vigorously overnightwith the addition of THF (15 mL). The mixture was filtered throughcelite, washing with excess EtOAc. The filtrate was concentrated invacuo. Purification of the residue by flash column chromatography onsilica (30%→50% EtOAc/Hex) afforded 254 mg (38%) of the desired alkene37.

Step 3. Metathesis Reaction of 37 to Give Alkene 38

Benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)-ruthenium(Grubbs' catalyst, 2nd generation, 48 mg, 0.057 mmol) was added to asolution of alkene 37 (230 mg, 0.56 mmol) and methyl5-allylthiophene-2-carboxylate (preparation 3, 206 mg, 1.13 mmol) inCH₂Cl₂ (3.0 mL). The reaction mixture was heated at reflux for 4 h. Thereaction mixture was cooled to rt and more catalyst (48 mg, 0.057 mmol)and methyl 5-allylthiophene-2-carboxylate (100 mg, 0.55 mmol) wereadded. The mixture was heated for 18 h longer at reflux then cooled andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica (5%→50% EtOAc/Hex, gradient) afforded 100 mg(32%) of the desired alkene 38 along with 130 mg (57%) of the startingalkene 37.

Step 4. Oxidative Deprotection of 38 to Give 39 and 40

DDQ (58 mg, 0.26 mmol) was added to a mixture of 38 (130 mg, 0.23 mmol)in CH₂Cl₂ (3.1 mL) and water (0.16 mL) at 0° C. under nitrogen. After 45min, the reaction was quenched with saturated aqueous NaHCO₃ (40 mL).The mixture was extracted with EtOAc (3×30 mL). The combined extractswere washed with brine (25 mL) then dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica (50%→75% EtOAc/Hex, gradient) afforded 28 mg ofan inseparable mixture of starting material 38 and ketone 39, and 63 mg(62%) of the desired alcohol 40.

Step 5. Saponification of 40 to Give 41

Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution ofester 40 (3.7 mg, 0.008 mmol) in MeCN (0.2 mL) and pH 7.2 buffer (2.5mL). After 15.5 h at rt, the reaction was diluted with MeCN (8 mL) andconcentrated in vacuo. The residue was suspended in 10% MeOH/CH₂Cl₂andfiltered through a cotton plug. The filtrate was concentrated in vacuoto afford 3.0 mg (84%) of the title compound (41).

EXAMPLE 175-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid (43)

Step 1. Hydrogenation of 40 to Give Ester 42

Palladium on carbon (10 wt. %, 15 mg) was added to a solution of alkene40 (63 mg, 0.14 mmol) in methanol (3.0 mL). A hydrogen atmosphere wasestablished by evacuating and refilling with hydrogen (3×) and thereaction mixture was stirred under a balloon of hydrogen. After 3 h atrt, the reaction mixture was filtered through celite, washing with MeOH,and the filtrate was concentrated in vacuo to afford 63 mg crudeproduct. ¹H NMR analysis showed starting material remaining so the crudematerial was resubmitted to the conditions above. After 20 h at rt, thereaction mixture was filtered through celite, washing with MeOH, and thefiltrate was concentrated in vacuo to afford 60 mg (95%) of the desiredester 42.

Step 2. Saponification of 42 to Give 43.

Aqueous 1 N lithium hydroxide (0.19 mL, 0.19 mmol) was added to asolution of ester 42 (17 mg, 0.038 mmol) in THF (0.38 mL). After 20 h atrt, H₂O (1.0 mL) was added and the mixture was acidified with 1 Naqueous HCl (1.0 mL) and extracted with EtOAc (3×10 mL). The combinedextracts were washed with brine (10 mL) then dried (Na₂SO₄), filteredand concentrated in vacuo. Purification of the residue by flash columnchromatography on silica (EtOAc→25% MeOH/EtOAc, gradient) afforded 14.4mg (87%) of the title compound (43).

EXAMPLE 185-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid isopropyl ester (44)

DBU (5.2 μL, 0.035 mmol) was added to a solution of acid 43 (7.5 mg,0.017 mmol) in acetone (0.1 mL) at rt under nitrogen. After 10 min,2-iodopropane (35 μL, 0.35 mmol) was added. After 21 h at rt, thereaction was quenched with 0.01 N HCl (3 mL) and extracted with EtOAc(3×4 mL). The combined extracts were washed with brine (5 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. Purification of theresidue by flash column chromatography on silica (CH₂Cl₂→1% MeOH/CH₂Cl₂)afforded 4.6 mg (53%) of the title compound (44).

EXAMPLE 195-{3-[(S)-1-(4-Hexanoyl-phenyl)-5-oxo-pyrrolidin-2-yl]-propyl}-thiophene-2-carboxylicacid (46)

Step 1. Oxidation of 38/39 Afford 39

DDQ (5.5 mg, 0.024 mmol) was added to the mixture of ether 38 and ketone39 from Example 16, step 4 (6.8 mg, 0.012 mmol) in CH₂Cl₂ and water(20:1, 0.25 mL) at rt under nitrogen. After 1.5 h, the reaction wasquenched with saturated aqueous NaHCO₃ (5 mL). The mixture was extractedwith EtOAc (3×5 mL). The combined extracts were washed with brine (5 mL)then dried (Na₂SO₄), filtered and concentrated in vacuo. Purification ofthe residue by preparative thin layer chromatography (60% EtOAc/Hex)afforded 1.5 mg (28%) of desired ketone 39.

Step 2. Hydrogenation of 39 to Give Ester 45

Palladium on carbon (10 wt. %, 1 mg) was added to a solution of alkene39 (1.5 mg, 0.0034 mmol) in methanol (0.5 mL). A hydrogen atmosphere wasestablished by evacuating and refilling with hydrogen (3×) and thereaction mixture was stirred under a balloon of hydrogen. After 2 h atrt, the reaction mixture was filtered through celite, washing with MeOH,and the filtrate was concentrated in vacuo to afford 1.3 mg (86%) ofdesired ester 45.

Step 3. Saponification of 45 to Give 46

Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution ofester 45 (1.3 mg, 0.0029 mmol) in MeCN (0.1 mL) and pH 7.2 buffer (2.5mL). After 23 h at rt, the reaction was diluted with MeCN (10 mL) andconcentrated in vacuo. The residue was suspended in 10% MeOH/CH₂Cl₂ andfiltered through a cotton plug. The filtrate was concentrated in vacuoto afford 1.2 mg (95%) of the title compound (46).

EXAMPLE 205-[(R)-1-(4-Hexanoyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylicacid (47)

Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution ofester 27 (Example 10, step 4, 6.6 mg, 0.014 mmol) in MeCN (0.1 mL) andpH 7.2 buffer (2.5 mL). After 17 h at rt, the reaction was diluted withMeCN (8 mL) and concentrated in vacuo. Purification of the residue bypreparative thin layer chromatography (4% MeOH/CH₂Cl₂) afforded 1 mg(17%) of the title compound (47).

EXAMPLES 21 AND 225-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid isopropyl ester (faster eluting diastereomer 48) and5-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid isopropyl ester (slower eluting diastereomer 49)

The two diastereomers of example 10 (28, ˜100 mg) were separated on aWaters 600 HPLC instrument employing a Waters 2996 PDA detector and aWhatman Partisil® 10 M20/50 column, 22 mm×500 mm (Cat. No. 4232-220,Q.A. No. 3TA02D80). Using 60% EtOAc/Hex as the eluent and a flow rate of15 mL/min, the first diastereomer (48, 32.8 mg total isolated) eluted at55-60 min, and the second diastereomer (49, 52.6 mg total isolated)eluted at 61-70 min.

EXAMPLE 235-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid (50)

Aqueous 1 N lithium hydroxide (0.05 mL, 0.05 mmol) was added to asolution of faster eluting ester diastereomer 48 (2.7 mg, 0.0057 mmol)in THF (0.1 mL) and the mixture was heated at reflux overnight. After 17h, the reaction was cooled to rt, acidified with 0.05 N aqueous HCl (5mL) and extracted with CH₂Cl₂ (3×5 mL). The combined extracts were dried(Na₂SO₄), filtered and concentrated in vacuo to afford 2.5 mg (100%) ofthe title compound (50).

EXAMPLE 245-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid (51)

Aqueous 1 N lithium hydroxide (0.05 mL, 0.05 mmol) was added to asolution of slower eluting ester diastereomer 49 (2.8 mg, 0.0059 mmol)in THF (0.1 mL) and the mixture was heated at reflux overnight. After 23h, the reaction was cooled to rt, acidified with 0.05 N aqueous HCl (5mL) and extracted with CH₂Cl₂ (3×5 mL). The combined extracts were dried(Na₂SO₄), filtered and concentrated in vacuo to afford 1.7 mg (67%) ofthe title compound (51).

EXAMPLES 25 AND 265-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid methyl ester (faster eluting diastereomer 52) and5-(3-{(S)-1-[4-(1-hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid methyl ester (slower eluting diastereomer 53)

The two diastereomers from example 17, step 1 (42, ˜43 mg) wereseparated on a Waters 600 HPLC instrument employing a Waters 2996 PDAdetector and a Whatman Partisil® 10 M20/50 column, 22 mm×500 mm (Cat.No. 4232-220, Q.A. No. 3TA02D80). Using 55% EtOAc/Hex as the eluent anda flow rate of 15 mL/min, the first diastereomer (52, 16 mg) eluted at69-75 min, and the second diastereomer (53, 19 mg) eluted at 80-88 min.

EXAMPLE 275-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid (54)

Rabbit liver esterase (134 units/mg, 2 mg) was added to a solution offaster eluting ester diastereomer 52 (16 mg, 0.036 mmol) in MeCN (0.2mL) and pH 7.2 buffer (3.0 mL). After 18 h at rt, the reaction wasdiluted with MeCN (10 mL) and concentrated in vacuo. The residue wasdiluted with CH₂Cl₂ (5 mL), filtered through a plug of glass wool andconcentrated in vacuo. Purification of the residue by preparative thinlayer chromatography (EtOAc→25% MeOH/EtOAc, gradient) afforded 12 mg(77%) of the title compound (54).

EXAMPLE 285-(3-(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid (55)

Rabbit liver esterase (134 units/mg, 2 mg) was added to a solution ofslower eluting ester diastereomer 53 (19 mg, 0.043 mmol) in MeCN (0.2mL) and pH 7.2 buffer (3.0 mL). After 18 h at rt, the reaction wasdiluted with MeCN (10 mL) and concentrated in vacuo. The residue wasdiluted with CH₂Cl₂ (5 mL), filtered through a plug of glass wool andconcentrated in vacuo. Purification of the residue by preparative thinlayer chromatography (EtOAc→25% MeOH/EtOAc, gradient) afforded 10.5 mg(57%) of the title compound (55).

EXAMPLE 295-(3-(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid isopropyl ester (56, from 54 and 52)

DBU (4.2 μL, 0.028 mmol) and 2-iodopropane (19 μL, 0.19 mmol) were addedto a solution of acid 54 (8 mg, 0.019 mmol) in acetone (0.15 mL) at rtunder nitrogen. After 18 h at rt, the solvent was removed under a streamof nitrogen. The residue was diluted with EtOAc (10 mL) and washed with0.1 N HCl (2×5 mL) and brine (5 mL) then dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica (CH₂Cl₂→25% MeOH/CH₂Cl₂) afforded 1.9 mg (22%)of the title compound (56) and 4 mg (50%) recovered 54.

EXAMPLE 305-(3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid isopropyl ester (57, from 55 and 53)

DBU (4.7 μL, 0.031 mmol) and 2-iodopropane (21 μL, 0.21 mmol) were addedto a solution of acid 55 (9 mg, 0.021 mmol) in acetone (0.2 mL) at rtunder nitrogen. After 18 h at rt, the solvent was removed under a streamof nitrogen. The residue was diluted with EtOAc (10 mL) and washed with0.1 N HCl (2×5 mL) and brine (5 mL) then dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica (CH₂Cl₂→25% MeOH/CH₂Cl₂) afforded 2.0 mg (20%)of the title compound (57) and 6 mg (67%) recovered 55.

EXAMPLE 315-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid isopropyl ester (61)

Step 1. Arylation of 1 to Give 58

Pd₂(dba)₃ (550 mg, 0.60 mmol), xantphos (1.04 g, 180 mmol) and Cs₂CO₃(5.87 g, 18.0 mmol) were added sequentially to a solution of amide 1(3.45 g, 15.0 mmol) in 1,4-dioxane (100 mL). A solution of1-(1-(4-methoxybenzyloxyheptyl)-4-bromobenzene (preparation 4, 5.30 g,13.54 mmol) in 1,4-dioxane (50 mL) was added via cannula. The reactionmixture was purged with nitrogen then heated at reflux overnight. After17 h, the reaction was cooled to rt and filtered through celite, washingwith CH₂Cl₂. The filtrate was concentrated in vacuo and the residue waspurified by flash column chromatography on silica gel (5%→35%EtOAc/Hexane, gradient) to afford 5.26 g (72%) of the desired product58.

Step 2. Deprotection of 58 to Give 59

HF-pyridine (8.8 mL) was added to a solution of silyl ether 58 (5.26 g,9.74 mmol) in MeCN (50 mL) in a plastic bottle at 0° C. After 45 min at0° C., the reaction was quenched with saturated aqueous NaHCO₃ (400 mL).The mixture was extracted with EtOAc (3×200 mL). The combined extractswere washed with brine (200 mL) then dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica (CH₂Cl₂→5% MeOH/CH₂Cl₂, gradient) afforded 3.9g (94%) of the desired alcohol 59 as a pale yellow solid.

Step 3. Alkylation of 59 to Give 60

A round bottom flask was charged with potassium hydride (30 wt % in oil,138 mg, 1.03 mmol). The material was washed with hexanes (3×1 mL), thensuspended in THF (1 mL). The mixture was cooled to 0° C. and a solutionof alcohol 59 (339 mg, 0.80 mmol) in THF (1.5 mL) was added via cannula.After 1 h at 0° C., a solution of isopropyl5-chloromethylthiophene-2-carboxylate (preparation 2, 174 mg, 0.80 mmol)in THF (1.5 mL) was added via cannula. Potassium iodide (14 mg, 0.08mmol) was added and the reaction was allowed to warm to rt. After 18 h,the reaction was quenched with saturated aqueous NH₄Cl (15 mL) andextracted with EtOAc (3×25 mL). Combined extracts were washed with brine(15 mL) then dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(20%→75% EtOAc/Hexane, gradient), followed by preparative thin layerchromatography (65% EtOAc/Hexane) afforded 65 mg (14%) of desiredproduct 60.

Step 4. Oxidative Deprotection of 60 to Give 61

DDQ (26 mg, 0.12 mmol) was added to a solution of 60 (65 mg, 0.11 mmol)in CH₂Cl₂ (1.4 mL) and water (0.07 mL) at 0° C. under nitrogen. After 40min, the reaction was quenched with saturated aqueous NaHCO₃ (20 mL) andextracted with EtOAc (3×20 mL). Combined extracts were washed with brine(15 mL) then dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(50%→75% EtOAc/Hexane, gradient), followed by preparative thin layerchromatography (60% EtOAc/Hexane) afforded 36 mg (69%) of the titlecompound (61).

EXAMPLES 32 AND 335-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid isopropyl ester (faster eluting diastereomer 62) and5-{(R)-1-[4-(1-hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid isopropyl ester (slower eluting diastereomer 63)

The two diastereomers of example 31 (61, ˜36 mg) were separated on aWaters 600 HPLC instrument employing a Waters 2996 PDA detector and aWhatman Partisil® 10 M20/50 column, 22 mm×500 mm (Cat. No. 4232-220,Q.A. No. 3TA02D80). Using 60% EtOAc/Hex as the eluent and a flow rate of15 mL/min, the first diastereomer (62, 14.8 mg) eluted at 50-56.5 min,and the second diastereomer (63, 16.4 mg) eluted at 56.5-70 min.

EXAMPLE 345-1(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid (64)

Aqueous 1 N lithium hydroxide (0.05 mL, 0.05 mmol) was added to asolution of faster eluting ester diastereomer 62 (3.5 mg, 0.0072 mmol)in THF (0.1 mL) and the mixture was heated at reflux overnight. After 18h, the reaction was cooled to rt, diluted with water (2 mL), acidifiedwith 1.0 N aqueous HCl (1 mL) and extracted with EtOAc (3×5 mL). Thecombined extracts were washed with brine (5 mL), dried (Na₂SO₄),filtered and concentrated in vacuo to afford 3.0 mg (94%) of the titlecompound (64).

EXAMPLE 355-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid (65)

Aqueous 1 N lithium hydroxide (0.05 mL, 0.05 mmol) was added to asolution of slower eluting ester diastereomer 63 (3.5 mg, 0.0072 mmol)in THF (0.1 mL) and the mixture was heated at reflux overnight. After 18h, the reaction was cooled to rt, diluted with water (2 mL), acidifiedwith 1.0 N aqueous HCl (1 mL) and extracted with EtOAc (3×5 mL). Thecombined extracts were washed with brine (5 mL), dried (Na₂SO₄),filtered and concentrated in vacuo to afford 3.2 mg (99%) of the titlecompound (65).

EXAMPLE 365-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid (71)

Step 1. Oxidation of 59 to Give Aldehyde 66

1-(3-(Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.43g, 7.45 mmol) and DMSO (0.70 mL, 9.86 mmol) were added sequentially to asolution of alcohol 59 (1.06 g, 2.48 mmol) in benzene (25 mL) at rtunder nitrogen. After 10 min at rt, pyridinium trifluoroacetate (527 mg,2.73 mmol) was added. After 3 h at rt, the solution was decanted fromthe oily residue and the residue was washed with benzene (3×15 mL). Thecombined benzene phases were concentrated in vacuo. Purification of theresidue by flash column chromatography on silica (CH₂Cl₂→3% MeOH/CH₂Cl₂,gradient) afforded 1.0 g (95%) of the desired aldehyde 66.

Step 2. Methylenation of 66 to Give Alkene 67

The Tebbe reagent (0.5 M in THF, 7.0 mL, 3.5 mmol) was added to asolution of aldehyde 66 (1.0 g, 2.36 mmol) in THF (16 mL) at −40° C.under nitrogen. After 1 h at −40° C. the reaction was quenched byaddition of aqueous 2 N NaOH (5.25 mL) and stirred vigorously overnightwith the addition of THF (20 mL). The mixture was filtered throughcelite, washing with excess EtOAc. The filtrate was concentrated invacuo. Purification of the residue by flash column chromatography onsilica (40% EtOAc/Hex) afforded 195 mg (20%) of the desired alkene 67.

Step 3. Metathesis Reaction of 67 to Give Alkene 68

Grubbs' second generation catalyst (38 mg, 0.045 mmol) was added to asolution of alkene 67 (190 mg, 0.45 mmol) and methyl5-allylthiophene-2-carboxylate (preparation 3, 173 mg, 0.95 mmol) inCH₂Cl₂ (2.4 mL). The reaction mixture was heated at reflux for 2 h. Thereaction mixture was cooled to rt and more catalyst (9 mg, 0.011 mmol)and methyl 5-allylthiophene-2-carboxylate (165 mg, 0.91 mmol) wereadded. The mixture was heated for 22 h longer at reflux then cooled andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica (2 times, first using 5%→50% EtOAc/Hex,gradient then second using CH₂Cl₂→3% MeOH/CH₂Cl₂, gradient) afforded 180mg (69%) of the desired alkene 68.

Step 4. Oxidative Deprotection of 68 to Give 69

DDQ (78 mg, 0.34 mmol) was added to a mixture of 68 (180 mg, 0.31 mmol)in CH₂Cl₂ (4.1 mL) and water (0.21 mL) at 0° C. under nitrogen. After 45min at 0° C., the reaction was quenched with saturated aqueous NaHCO₃(50 mL). The mixture was extracted with EtOAc (3×50 mL). The combinedextracts were washed with brine (50 mL) then dried (Na₂SO₄), filteredand concentrated in vacuo. Purification of the residue by flash columnchromatography on silica (50%→66% EtOAc/Hex, gradient) afforded 50 mg(35%) of the desired alcohol 69.

Step 5. Hydrogenation of 69 to Give Ester 70

Palladium on carbon (10 wt. %, 12 mg) was added to a solution of alkene69 (50 mg, 0.11 mmol) in methanol (2.3 mL). A hydrogen atmosphere wasestablished by evacuating and refilling with hydrogen (3×) and thereaction mixture was stirred under a balloon of hydrogen. After 20 h atrt, the reaction mixture was filtered through celite, washing with MeOH,and the filtrate was concentrated in vacuo to afford 50 mg (99%) of thedesired ester 70.

Step 6. Saponification of 70 to Give 71

Aqueous 1 N lithium hydroxide (0.19 mL, 0.19 mmol) was added to asolution of ester 70 (17 mg, 0.038 mmol) in THF (0.4 mL). After 18 h atrt, H₂O (1.0 mL) was added and the mixture was acidified with 1 Naqueous HCl (1.0 mL) and extracted with EtOAc (3×10 mL). The combinedextracts were washed with brine (10 mL) then dried (Na₂SO₄), filteredand concentrated in vacuo. Purification of the residue by preparativethin layer chromatography (15% MeOH/CH₂Cl₂) afforded 5.6 mg (34%) of thetitle compound (71).

EXAMPLES 37 AND 385-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid methyl ester (faster eluting diastereomer 72) and5-(3-{(S)-1-[4-(1-hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid methyl ester (slower eluting diastereomer 73)

The two diastereomers from example 36, step 5 (70, ˜34 mg) wereseparated on a Waters 600 HPLC instrument employing a Waters 2996 PDAdetector and a Whatman Partisil® 10 M20/50 column, 22 mm×500 mm (Cat.No. 4232-220, Q.A. No. 3TA02D80). Using 55% EtOAc/Hex as the eluent anda flow rate of 15 mL/min, the first diastereomer (72, 10.7 mg) eluted at78-87.5 min, and the second diastereomer (73, 7.0 mg) eluted at 91-101min.

EXAMPLE 395-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid (74)

Aqueous 1 N lithium hydroxide (0.12 mL, 0.12 mmol) was added to asolution of faster eluting ester diastereomer 72 (10.7 mg, 0.023 mmol)in THF (0.3 mL). After 66 h at rt, H₂O (1.0 mL) was added and themixture was acidified with 1 N aqueous HCl (1.0 mL) and extracted withEtOAc (3×10 mL). The combined extracts were washed with brine (5 mL)then dried (Na₂SO₄), filtered and concentrated in vacuo to afford 10 mg(96%) of the title compound (74).

EXAMPLE 405-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid (75)

Aqueous 1 N lithium hydroxide (0.08 mL, 0.08 mmol) was added to asolution of slower eluting ester diastereomer 73 (7.0 mg, 0.015 mmol) inTHF (0.2 mL). After 66 h at rt, H₂O (1.0 mL) was added and the mixturewas acidified with 1 N aqueous HCl (1.0 mL) and extracted with EtOAc(3×8 mL). The combined extracts were washed with brine (5 mL) then dried(Na₂SO₄), filtered and concentrated in vacuo to afford 6.5 mg (96%) ofthe title compound (75).

EXAMPLE 415-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid isopropyl ester (76, from 74 and 72)

DBU (4.0 μL, 0.027 mmol) and 2-iodopropane (36 μL, 0.36 mmol) were addedto a solution of acid 74 (8 mg, 0.018 mmol) in acetone (0.2 mL) at rtunder nitrogen. After 72 h at rt, the solvent was removed under a streamof nitrogen. The residue was diluted with EtOAc (10 mL) and washed with0.5 N HCl (2×5 mL) and brine (5 mL) then dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica (EtOAc→20% MeOH/EtOAc) afforded 7.3 mg (83%) ofthe title compound (76).

EXAMPLE 425-(3-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid isopropyl ester (77, from 75 and 73)

DBU (2.5 μL, 0.017 mmol) and 2-iodopropane (22.5 μL, 0.225 mmol) wereadded to a solution of acid 75 (5 mg, 0.011 mmol) in acetone (0.11 mL)at rt under nitrogen. After 72 h at rt, the solvent was removed under astream of nitrogen. The residue was diluted with EtOAc (10 mL) andwashed with 0.5 N HCl (2×5 mL) and brine (5 mL) then dried (Na₂SO₄),filtered and concentrated in vacuo. Purification of the residue by flashcolumn chromatography on silica (EtOAc→20% MeOH/EtOAc) afforded 3.2 mg(58%) of the title compound (77).

EXAMPLE 434-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxy}-benzoicacid (80)

Step 1. Mitsunobu Reaction of 25 and Methyl 4-Hydroxybenzoate to Give 78

Diisopropyl azodicarboxylate (DIAD, 194 μL, 1.0 mmol) was added to asolution of alcohol 25 (200 mg, 0.49 mmol), triphenylphosphine (191 mg,0.73 mmol) and methyl 4-hydroxybenzoate (87 mg, 0.57 mmol) in CH₂Cl₂(2.5 mL). After stirring 18 h at rt, the solvent was removed under astream of nitrogen and the residue was suspended in EtOAc (75 mL). Themixture was washed with saturated aqueous NaHCO₃ (3×25 mL) and brine (25mL) then the organic phase was dried (Na₂SO₄) filtered and concentratedin vacuo. Purification of the residue by flash column chromatography onsilica gel (50% EtOAc/hexane→EtOAc, gradient) afforded 81 mg (31%) ofthe desired ether 78.

Step 2. Oxidative Deprotection of 78 to Give 79

DDQ (37 mg, 0.16 mmol) was added to a mixture of 78 (81 mg, 0.15 mmol)in CH₂Cl₂ (2.0 mL) and water (0.1 mL) at 0° C. under nitrogen. After 45min at 0° C., the reaction was quenched with saturated aqueous NaHCO₃(25 mL). The mixture was extracted with EtOAc (3×25 mL). The combinedextracts were washed with brine (25 mL) then dried (Na₂SO₄), filteredand concentrated in vacuo. Purification of the residue by flash columnchromatography on silica (85% EtOAc/Hex→EtOAc, gradient) afforded 31 mg(49%) of the desired alcohol 79.

Step 3. Saponification of 79 to Give 80

Aqueous 1 N lithium hydroxide (0.35 mL, 0.35 mmol) was added to asolution of ester 79 (30 mg, 0.071 mmol) in THF (0.7 mL). After 20 h atrt, water (2.0 mL) was added and the mixture was acidified with 1 Naqueous HCl (1.5 mL) and extracted with EtOAc (3×10 mL). The combinedextracts were washed with brine (10 mL) then dried (Na₂SO₄), filteredand concentrated in vacuo. Purification of the residue by flash columnchromatography on silica (EtOAc→10% MeOH/EtOAc, gradient) afforded 11.5mg (38%) of starting ester 79 and 8.5 mg (29%) of the title compound(80).

Preparation 1 1-(1-(4-Methoxybenzyloxy-hexyl)-4-bromobenzene

Step 1. Pentyl Grignard Addition to 4-Bromobenzaldehyde

n-Pentyl magnesium bromide (2.0 M in THF, 27 mL, 54 mmol) was added to asolution of 4-bromobenzaldehyde (5.0 g, 27 mmol) in THF (20 mL) at 0° C.under nitrogen. After 1 h, the reaction was quenched with 3 N HCl andextracted with Et₂O (3×120 mL). Combined extracts were washed with brine(100 mL), dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(5% EtOAc/Hex) afforded 5.1 g (74%) of 1-(4-bromophenyl)-hexan-1-ol.

Step 2. Protection of the Alcohol as its MPM Ether

Sodium hydride (60% wt. in oil, 0.95 g, 23.8 mmol) was added to asolution of the alcohol from step 1 (5.11 g, 19.9 mmol) in THF and DMF(2:1, 20 mL) at 0° C. under nitrogen. After 1 h at 0° C.,4-methoxybenzyl chloride (3.23 mL, 23.8 mmol) and the reaction wasallowed to warm to rt. The reaction was then heated at 80° C. After 17h, the reaction was allowed to cool to rt, quenched with saturatedaqueous NH₄Cl (100 mL) and extracted with EtOAc (3×100 mL). The combinedextracts were washed with brine (100 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica gel (2% EtOAc/Hex) afforded 7.02 g (94%) of thetitle compound.

Preparation 2 Isopropyl 5-chloromethylthiophene-2-carboxylate

Step 1. Preparation of the Bis-Isopropyl Ester

DBU (31.3 mL, 209 mmol) and 2-iodopropane (20.9 mL, 209 mmol) were addedto a solution of thiophene-2,5-dicarboxylic acid (6.0 g, 34.9 mmol) inacetone (60 mL) at rt under nitrogen. After 21 h at rt, the reaction wasquenched with saturated aqueous NaHCO₃ (300 mL) and extracted with EtOAc(3×150 mL). The combined extracts were washed with brine (200 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to afford 7.59g (85%) ofthe diester.

Step 2. Reduction to the Hydroxymethyl Ester

Sodium borohydride (3.36 g, 88.8 mmol) was added to a solution of thediester (7.59 g, 29.6 mmol) in CH₂Cl₂/MeOH (1:1, 100 mL) at 0° C. undernitrogen. The ice bath was removed and the reaction was allowed to stirat rt overnight. After 20.5 h at rt the reaction was concentrated invacuo then aqueous 0.5 N HCl (100 mL) was added. The mixture wasextracted with CH₂Cl₂ (3×100 mL). The combined extracts were dried(Na₂SO₄), filtered and concentrated in vacuo. Purification of theresidue by flash column chromatography on silica (5% 60% EtOAc/Hex,gradient) afforded 738 mg (12%) of the alcohol.

Step 3. Conversion of the Alcohol to the Chloride

Methanesulfonyl chloride (0.67 mL, 8.1 mmol) and triethylamine (1.7 mL,12.2 mmol) were added sequentially and dropwise to a solution of thealcohol (696 mg, 3.48 mmol) in CH₂Cl₂ (4.0 mL) at 0° C. under nitrogen.The ice bath was removed and the reaction was allowed to stir overnightat rt. After 17 h, the reaction was quenched with saturated aqueousNaHCO₃ (30 mL) and extracted with CH₂Cl₂ (3×50 mL). The combinedextracts were dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica (5%EtOAc/Hex) afforded 664 mg (87%) of the title compound.

Preparation 3 Methyl 5-allylthiophene-2-carboxylate

Step 1. Preparation of the Methyl Ester

Acetyl chloride (6.9 mL, 96.6 mmol) was added to a solution of5-bromo-2-thiophenecarboxylic acid (4.0 g, 19.3 mmol) in methanol (30mL) at rt. After 17 h at rt, the reaction was heated at reflux for 1.5 hto drive it to completion. The reaction was then cooled to rt andconcentrated in vacuo to remove methanol. Saturated aqueous NH₄Cl (120mL) was added and the mixture was extracted with CH₂Cl₂ (3×100 mL). Thecombined extracts were dried (Na₂SO₄), filtered and concentrated invacuo to afford 3.57 g (84%) of the desired methyl ester as an off whitesolid.

Step 2. Allylation of the Bromothiophene

Isopropyl magnesium chloride (2.0 M in Et₂O, 8.9 mL, 17.8 mmol) wasadded to a solution of the bromide from step 1 (3.56 g, 16.1 mmol) inTHF (10 mL) at −40° C. under nitrogen. The reaction mixture was stirredat −40° C. for 1 h, then copper (I) cyanide (144 mg, 1.61 mmol) andallyl bromide (3.0 mL, 35.4 mmol) were added sequentially. The reactionmixture was stirred at −40° C. for 1 h then was quenched with saturatedaqueous NH₄Cl (100 mL) and extracted with EtOAc (3×100 mL). The combinedextracts were washed with brine (100 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica gel (5% EtOAc/Hex) afforded 2.45 g (83%) of thetitle compound as a pale yellow oil that solidified on standing.

Preparation 4 1-(1-(4-Methoxybenzyloxy-heptyl)-4-bromobenzene

Step 1. Hexyl Grignard Addition to 4-Bromobenzaldehyde

n-Hexyl magnesium bromide (2.0 M in Et₂O, 27 mL, 54 mmol) was added to asolution of 4-bromobenzaldehyde (5.0 g, 27 mmol) in THF (20 mL) at 0° C.under nitrogen. After 1.5 h at 0° C., the reaction was quenched slowlywith 3 N HCl (20 mL) and concentrated in vacuo. The residue was dilutedwith water (30 mL) and extracted with Et₂O (3×150 mL). Combined extractswere dried (Na₂SO₄), filtered and concentrated in vacuo. Purification ofthe residue by flash column chromatography on silica gel (5%→10%EtOAc/Hex) afforded 5.6 g (76%) of 1-(4-bromophenyl)-heptan-1-ol.

Step 2. Protection of the Alcohol as its MPM Ether

Sodium hydride (60% wt. in oil, 0.991 g, 24.8 mmol) was added to asolution of the alcohol from step 1 (5.6 g, 20.6 mmol) in THF and DMF(2:1, 30 mL) at 0° C. under nitrogen. After 5 min at 0° C., the reactionwas allowed to warm to rt and 4-methoxybenzyl chloride (3.4 mL, 25.0mmol) was added. The reaction was then heated at 80° C. After 18 h at80° C., the reaction was allowed to cool to rt, quenched with saturatedaqueous NH₄Cl (50 mL) and concentrated in vacuo. The remainder wasextracted with EtOAc (3×100 mL). The combined extracts were washed withwater (2×100 mL) and brine (75 mL), then dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica gel (2% EtOAc/Hex) afforded 7.5 g (93%) of thetitle compound.

EP2 data EP4 data Other Receptors (EC50 Ki flipr cAMP pH flipr StructureEC50 EC50 Ki 6.0 EC50 KI hFP hEP1 hEP3A hTP

>10000 NA >10000 >10000

>10000 NA >10000 >10000

442 28 4000 189 >10000 >10000 NA NA >10000 NA

1343 51 501 27 >10000 >10000 NA >10000 19234 >10000

4121 548 >10000 >10000 >10000 NA >10000 19544 NA

388 26 2028 NA >10000 NA NA 1927 NA

7669 1218 >10000 NA >10000 NA NA NA NA

1228 148 2293 NA >10000 NA NA NA NA

8 3 115 >10000 >10000 NA NA 403 NA

>10000 517 NA NA >10000 NA NA NA NA

212 8 387 NA >10000 NA NA NA NA

20 1.5 190 NA >10000 NA NA 519 NA

426 27 1639 NA >10000 NA NA NA NA

1812 312 5731 >10000 >10000 NA NA NA NA

226 15 1382 NA >10000 NA NA 1411 NA

5 0.55 23 NA >10000 NA NA 155 NA

16 1.6 31 >10000 >10000 NA NA 2345 NA

215 8 163 NA >10000 NA NA NA NA

62 5 345 >10000 >10000 NA NA 153 NA

15 1.5 116 >10000 6032 NA NA 1205 NA

6 0.19 21 >10000 >10000 NA NA 12 NA

1.6 0.15 15 >10000 4849 NA NA 156 NA

134 7 229 NA 3842 NA NA 71 NA

49 4 201 NA 3288 NA NA 621 NA

30 0.9 10 >10000 NA NA 47 NA

16 1.4 12 NA NA 6952 7 NA

5 0.6 8 NA NA NA 33 NA

7284 NA 22726 NA 8752 NA NA NA NA

Biological Assay Methods Binding Data Ki

Competition binding experiments were performed in a medium containingHank's balanced salt solution, Hepes 20 mM, pH 7.3, membranes (˜60 μgprotein) or 2×10⁵ cells from HEK 293 cells stably expressing human EP2receptors, [³H]PGE2 (10 nM) and various concentrations of test compoundsin a total volume of 300 Reaction mixtures were incubated at 23° C. for60 min, and were filtered over Whatman GF/B filters under vacuum.Filters were washed three times with 5 ml ice-cold buffer containing 50mM Tris/HCl (pH 7.3). Non-specific binding was estimated in the presenceof excess unlabeled PGE2 (10 μM). Binding data fitted to the bindingmodel for a single class of binding sites, using nonlinear regressionanalysis. IC₅₀ values thus obtained were converted to Ki using theequation of Ki=(IC₅₀/(1+[L]/K_(D)) where [L] represents PGE2concentration (10 nM) and K_(D) the dissociation constant for [³H]PGE2at human EP2 receptors (40 nM).

Radioligand Binding Cells Stably Expressing EP_(1,) EP₂, EP₄ and FPReceptors

HEK-293 cells stably expressing the human or feline FP receptor, or EP₁,EP₂, or EP₄ receptors were washed with TME buffer, scraped from thebottom of the flasks, and homogenized for 30 sec using a Brinkman PT10/35 polytron. TME buffer was added to achieve a final 40 ml volume inthe centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mMMgCl₂, 2M EDTA; 10N HCl is added to achieve a pH of 7.4).

The cell homogenate was centrifuged at 19000 r.p.m. for 20 min at 4° C.using a Beckman Ti-60 rotor. The resultant pellet was resuspended in TMEbuffer to give a final 1 mg/ml protein concentration, as determined byBiorad assay. Radioligand binding competition assays vs. [³H-]17-phenylPGF_(2α) (5 nM) were performed in a 100 μl volume for 60 min. Bindingreactions were started by adding plasma membrane fraction. The reactionwas terminated by the addition of 4 ml ice-cold TRIS-HCl buffer andrapid filtration through glass fiber GF/B filters using a Brandel cellharvester. The filters were washed 3 times with ice-cold buffer and ovendried for one hour.

[³H-]PGE₂ (specific activity 180 Ci mmol) was used as the radioligandfor EP receptors. [³H] 17-phenyl PGF_(2α) was employed for FP receptorbinding studies. Binding studies employing EP₁, EP₂, EP₄ and FPreceptors were performed in duplicate in at least three separateexperiments. A 200 μl assay volume was used. Incubations were for 60 minat 25° C. and were terminated by the addition of 4 ml of ice-cold 50 mMTRIS-HCl, followed by rapid filtration through Whatman GF/B filters andthree additional 4 ml washes in a cell harvester (Brandel). Competitionstudies were performed using a final concentration of 5 nM [³H]-PGE₂, or5 nM [³H] 17-phenyl PGF_(2α) and non-specific binding determined with10⁻⁵M of unlabeled PGE₂, or 17-phenyl PGF_(2α), according to receptorsubtype studied.

Methods for FLIPR™ Studies (a) Cell Culture

HEK-293(EBNA) cells, stably expressing one type or subtype ofrecombinant human prostaglandin receptors (prostaglandin receptorsexpressed: hDP/Gqs5; hEP₁; hEP₂/Gqs5; hEP_(3A)/Gqi5; hER₄/Gqs5; hFP;hIP; hTP), were cultured in 100 mm culture dishes in high-glucose DMEMmedium containing 10% fetal bovine serum, 2 mM 1-glutamine, 250 μg/mlgeneticin (G418) and 200 μg/ml hygromycin B as selection markers, and100 units/ml penicillin G, 100 μg/ml streptomycin and 0.25 μg/mlamphotericin B.

(b) Calcium Signal Studies on the FLIPR™

Cells were seeded at a density of 5×10⁴ cells per well in Biocoat®Poly-D-lysine-coated black-wall, clear-bottom 96-well plates(Becton-Dickinson) and allowed to attach overnight in an incubator at37° C. Cells were then washed two times with HBSS-HEPES buffer (HanksBalanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES,pH 7.4) using a Denley Cellwash plate washer (Labsystems). After 45minutes of dye-loading in the dark, using the calcium-sensitive dyeFluo-4 AM at a final concentration of 2 μM, plates were washed fourtimes with HBSS-HEPES buffer to remove excess dye leaving 100 μl in eachwell. Plates were re-equilibrated to 37° C. for a few minutes.

Cells were excited with an Argon laser at 488 nm, and emission wasmeasured through a 510-570 nm bandwidth emission filter (FLIPR™,Molecular Devices, Sunnyvale, Calif.). Drug solution was added in a 50μl volume to each well to give the desired final concentration. The peakincrease in fluorescence intensity was recorded for each well. On eachplate, four wells each served as negative (HBSS-HEPES buffer) andpositive controls (standard agonists: BW245C (hDP); PGE₂ (hEP₁;hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5); PGF_(2α) (hFP); carbacyclin (hIP);U-46619 (hTP), depending on receptor). The peak fluorescence change ineach drug-containing well was then expressed relative to the controls.

Compounds were tested in a high-throughput (HTS) orconcentration-response (CoRe) format. In the HTS format, forty-fourcompounds per plate were examined in duplicates at a concentration of10⁻⁵ M. To generate concentration-response curves, four compounds perplate were tested in duplicates in a concentration range between 10⁻⁵and 10⁻¹¹ M. The duplicate values were averaged. In either, HTS or CoReformat each compound was tested on at least 3 separate plates usingcells from different passages to give an n≧3.

Intraocular Pressure (IOP)

Intraocular pressure studies in dogs involve pneumatonometry performedon conscious Beagle dogs of both sexes (10-15 kg). The animals remainconscious throughout the study and are gently restrained by hand. Drugsare administered topically to one eye as a 25 μL volume drop, the othereye receives 25 μL vehicle (0.1% polysorbate 80:10 mM TRIS) as acontrol. Proparacaine (0.1%) is used for corneal anesthesia duringtonometry. Intraocular pressure is determined just before drugadministration and at 2, 4 and 6 hr thereafter on each day of the 5 daystudy. Drug is administered immediately after the first IOP reading.

The results of the binding and activity studies, presented in Table 1below, demonstrate that the compounds disclosed herein are selectiveprostaglandin EP₂ agonists, and are thus useful for the treatment ofglaucoma, ocular hypertension, inflammatory bowel disease, and the otherdiseases or conditions disclosed herein.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

1. A method for treating inflammation comprising administering to asubject in need thereof a therapeutically effective amount of a compoundhaving the structure

or a pharmaceutically acceptable salt thereof; wherein A is —(CH₂)₆—,cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atomsmay be substituted with S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—whereinAr is interarylene or heterointerarylene, the sum of m and o is from 1to 4, and wherein one CH₂ may be substituted with S or O; R₁ is C₁ to C₆alkyl; and B is optionally substituted aryl or optionally substitutedheteroaryl.
 2. The method of claim 1 wherein B is phenyl.
 3. The methodof claim 2 wherein B is alkylphenyl.
 4. The method of claim 2 wherein Bis p-t-butylphenyl.
 5. The method of claim 2 wherein B ishydroxyalkylphenyl.
 6. The method of claim 1 wherein R₁ is C₃ alkyl. 7.The method of claim 1 wherein the compound has the structure:


8. The method of claim 1 wherein the compound has the structure:


9. The method of claim 1 wherein the compound has the structure

or a pharmaceutically acceptable salt thereof; wherein G is1,3-interaryl or interheteroaryl, or —(CH₂)₃—; R₁ is C₁ to C₆ alkyl; andB is optionally substituted aryl or optionally substituted heteroaryl.10. The method of claim 9 wherein B is phenyl.
 11. The method of claim10 wherein B is alkylphenyl.
 12. The method of claim 10 wherein B isp-t-butylphenyl.
 13. The method of claim 10 wherein B ishydroxyalkylphenyl.
 14. The method of claim 9 wherein R, is C₃ alkyl.15. The method of claim 1 wherein the compound has the structure

or a pharmaceutically acceptable salt thereof; wherein a dashed lineindicates the presence or absence of a bond; R₁ is C₁ to C₆ alkyl; R₂ isC₁ to C₁₂ hydrocarbyl or C₁ to C₁₂ hydroxyhydrocarbyl; X is CH₂, O, orS; and G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—.
 16. Themethod of claim 15, wherein R₁ is C₃ alkyl.
 17. The method of claim 15wherein R₁ is isopropyl.